Effect of Smoking on Endocrine Therapy for Stage IV Hormone Receptor Positive Breast Cancer

Effect of Smoking on Endocrine Therapy for Stage IV Hormone Receptor Positive Breast Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of Smoking on Endocrine Therapy for Stage IV Hormone Receptor Positive Breast Cancer Koji Takada, Shinichiro Kashiwagi, Akimichi Yabumoto, Nozomi Iimori, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1365423/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 Background : Smoking worsens breast cancer prognosis. It has been reported that tobacco components directly reach mammary gland tissue, causing smoking-related DNA damage and biological effects. We hypothesized that smoking may have a characteristic course other than the therapeutic effect in patients with stage IV hormone receptor-positive breast cancer (HRBC) who received endocrine therapy as the first-line treatment. Methods : Fifty-six patients diagnosed with stage IV HRBC were treated with endocrine therapy as the first-line treatment. Before treatment, the period and amount of smoking were confirmed through patient interviews, and each pack-year was recorded. Results : It was significantly more frequent for smokers to be evaluated for disease progression due to the appearance of new metastases during endocrine therapy as first-line treatment (p=0.034). Furthermore, as the pack-year increased, new metastases tended to appear (pack-year ≤15; hazard ratio [HR] 1.929, p=0.507; pack-year 15–30, HR 3.857, p=0.223; pack-year >30, HR: 7.714, p=0.028). Conclusions : In stage IV HRBC, smoking increases the metastatic potential of breast cancer, suggesting that changes in its biology may lead to poor prognosis. breast cancer smoking hormone receptor endocrine therapy cigarette Figures Figure 1 Figure 2 Background One of the important aspects of breast cancer treatment strategies for distant metastases is prolonging survival while maintaining a good quality of life. Therefore, in the past, the treatment of non-life-threatening hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer with distant metastases was often initiated with endocrine therapy using the Hortobagyi algorithm [ 1 ]. However, breast cancer may progress rapidly even with endocrine therapy. Smoking is recognized as a carcinogenic risk factor for breast cancer [ 2 ]. Additionally, it has been reported to worsen breast cancer [ 3 – 7 ] as the tobacco components directly reach mammary gland tissue, causing smoking-related DNA damage and biological changes [ 8 , 9 ]. These biological changes have led to more malignant tumors [ 10 , 11 ]. Therefore, we hypothesized that smoking may have a distinct course other than the therapeutic effect in patients with stage IV hormone receptor-positive breast cancer (HRBC) who received endocrine therapy as the first-line treatment. Methods Patient background From November 2007 to September 2017, 56 patients diagnosed with stage IV HRBC started endocrine therapy as the first-line treatment at Osaka City University Hospital. Before treatment, the period and amount of smoking were confirmed by interviewing the patients, and each pack-year was recorded. However, one patient was excluded from this study because of the unknown smoking history details. All patients underwent biopsy before treatment and were histologically diagnosed with breast cancer. In addition, the expression of the estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was evaluated through immunohistochemical staining of the biopsy tissue. Breast cancer with positive ER and/or PgR expression was defined as HRBC. Breast cancer staging was evaluated using ultrasonography, computed tomography, and bone scintigraphy. Subsequently, physical and imaging examinations were performed as needed in the outpatient department. Therapeutic effects were evaluated according to the Response Evaluation Criteria in Solid Tumors [ 12 ]. In this study, patients with clinical partial and complete responses based on the objective response rate were defined as “responders.” Meanwhile, those with clinical stable and progressive diseases were as classified as “non-responders” in objective response rate (ORR). The median follow-up period was 1539 days (range, 9–4479 days). Statistical analysis All statistical analyses were performed using the JMP software package (SAS, Tokyo, Japan). The relationship between each factor was examined using a χ2 test. The progression-free survival (PFS) and overall survival (OS) were compared using the Kaplan-Meier method and log-rank test. Hazard ratios (HRs) and 95% confidence intervals were calculated using the Cox proportional hazards model. Multivariate analysis was performed using the Cox regression model. Statistical significance was defined as a p-value less than 0.05. Results Clinicopathological features Table 1 shows the clinicopathological features of the 55 patients with stage IV HRBC who received endocrine therapy as first-line treatment. The median age of the patients was 63 (range, 38–89) years. The median tumor diameter was 40.7 mm (range, 9.2–146.3 mm), and 37 patients (67.3%) had skin infiltration. The absence of swelling regional lymph nodes was observed in only seven patients (12.7%). There were several cases of bone (34 cases, 61.8%) and lung metastases (31 cases, 56.4%). Twenty-five patients (45.5%) had metastasis to multiple organs. All patients with bone metastases received zoledronic acid or denosumab in combination with endocrine therapy. Fifty-three patients (96.4%) had ER-positive breast cancer, while 35 (63.6%) had PgR-positive breast cancer. Furthermore, 33 patients (60.0%) had both ER-and PgR-positive breast cancer. There were two patients with HER2-positive breast cancers (3.6%), but they did not receive anti-HER2 molecule-targeted drugs, such as trastuzumab. Ki67 was highly expressed in 18 patients (32.7%). Letrozole was the most commonly used primary endocrine therapy in 31 cases (56.4%). All 11 premenopausal patients (20.0%) were treated with luteinizing hormone-releasing hormone agonists and tamoxifen. Based on the ORR, 37 patients (67.3%) were evaluated as “responders”. Regarding smoking, 39 patients (70.9%) were nonsmokers. The median pack-years of the 16 smokers was 21.0 (range; 1.5–48.0). Table 1 Clinicopathological features of HRBC patients with distant metastasis who received endocrine therapy as the primary treatment. Parameters Number of all patients ( n = 55) (%) Number of patients whose disease progresses during endocrine therapy ( n = 50) (%) Age (years old) 63 (38–89) 62 (38–88) Tumor size (mm) 40.7 (9.2–146.3) 42.5 (11.8–146.3) Skin infiltration Negative / Positive 18 (32.7%) / 37 (67.3%) 17 (34.0%) / 33 (66.0%) Lymph node metastasis Negative / Positive 7 (12.7%) / 48 (87.3%) 5 (10.0%) / 45 (90.0%) The number of distant metastatic organs 1 / 2 / 3 / 4 30 (54.5%) / 17 (30.9%) / 7 (12.7%) / 1 (1.8%) 26 (52.0%) / 16 (32.0%) / 7 (14.0%) / 1 (2.0%) Site of metastases Bone / Lung / Liver / Skin / Brain / Distant lymph node 34 (61.8%) / 31 (56.4%) / 7 (12.7%) / 1 (1.8%) / 1 (1.8%) / 15 (27.3%) 30 (60.0%) / 29 (58.0%) / 7 (14.0%) / 1 (2.0%) / 1 (2.0%) / 15 (30.0%) Hormone receptor Both ER and PgR+ / only ER+ / only PgR+ 33 (60.0%) / 20 (36.4%) / 2 (3.6%) 29 (58.0%) / 19 (38.0%) / 2 (4.0%) HER2 Negative / Positive 53 (96.4%) / 2 (3.6%) 48 (96.0%) / 2 (4.0%) Ki67 Low / High 37 (67.3%) / 18 (32.7%) 33 (66.0%) / 17 (34.0%) Endocrine therapy LET / ANA / LH-RH agonist + TAM / EXE 31 (56.4%) / 12 (21.8%) / 11 (20.0%) / 1 (1.8%) 31 (62.0%) / 7 (14.0%) / 11 (22.0%) / 1 (2.0%) Objective response rate Non-Responders / Responders 18 (32.7%) / 37 (67.3%) 18 (36.0%) / 32 (64.0%) Criteria for disease progression No disease progression / Increased of existing tumor / Appearance of new metastasis 5 (9.1%) / 35 (63.6%) / 15 (27.3%) 35 (70.0%) / 15 (30.0%) Smoker No / Yes 39 (70.9%) / 16 (29.1%) 34 (68.0%) / 16 (32.0%) Pack-years of smoker 21.0 (1.5–48.0) 21.0 (1.5–48.0) HRBC: hormone receptor-positive breast cancer. ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LET: letrozole. ANA: anastrozole. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen. EXE: exemestane. Correlations Between The Clinicopathological Features And Smoking The correlation between the patients’ clinicopathological features and smoking status was also examined (Table 2 ). The smokers were significantly younger than the non-smokers (p = 0.029). Breast cancer in smokers had a significantly larger tumor diameter (p = 0.017) and significantly less frequent ER positivity (p = 0.005) than that in non-smokers. Table 2 Correlation between clinicopathological features and smoke in stage 4 HRBC patients. Parameters All patients p value Patients whose disease progresses during endocrine therapy p value Non-smoker ( n = 39) Smoker ( n = 16) Non-smoker ( n = 34) Smoker ( n = 16) Age (years old) ≤ 60 > 60 12 (30.8%) 27 (69.2%) 10 (62.5%) 6 (37.5%) 0.029 12 (35.3%) 22 (64.7%) 10 (62.5%) 6 (37.5%) 0.071 Tumor size (mm) ≤ 50.0 > 50.0 28 (71.8%) 11 (28.2%) 6 (37.5%) 10 (62.5%) 0.017 24 (70.6%) 10 (29.4%) 6 (37.5%) 10 (62.5%) 0.026 Skin infiltration Negative Positive 15 (38.5%) 24 (61.5%) 3 (18.8%) 13 (81.3%) 0.157 14 (41.2%) 20 (58.8%) 3 (18.8%) 13 (81.3%) 0.118 Lymph node metastasis Negative Positive 6 (15.4%) 33 (84.6%) 1 (6.3%) 15 (93.8%) 0.356 4 (11.8%) 30 (88.2%) 1 (6.3%) 15 (93.8%) 0.544 The number of distant metastatic organs Single Multiple 22 (56.4%) 17 (43.6%) 8 (50.0%) 8 (50.0%) 0.665 18 (52.9%) 16 (47.1%) 8 (50.0%) 8 (50.0%) 0.846 Bone metastases No Yes 13 (33.3%) 26 (66.7%) 8 (50.0%) 8 (50.0%) 0.248 12 (35.3%) 22 (64.7%) 8 (50.0%) 8 (50.0%) 0.322 Lung metastases No Yes 19 (48.7%) 20 (51.3%) 5 (31.3%) 11 (68.8%) 0.235 16 (47.1%) 18 (52.9%) 5 (31.3%) 11 (68.8%) 0.291 Liver metastases No Yes 36 (92.3%) 3 (7.7%) 12 (75.0%) 4 (25.0%) 0.080 31 (91.2%) 3 (8.8%) 12 (75.0%) 4 (25.0%) 0.124 Estrogen receptor Negative Positive 0 (0.0%) 39 (100.0%) 3 (18.8%) 13 (81.3%) 0.005 0 (0.0%) 34 (100.0%) 3 (18.8%) 13 (81.3%) 0.009 Progesterone receptor Negative Positive 14 (35.9%) 25 (64.1%) 7 (43.8%) 9 (56.3%) 0.586 13 (38.2%) 21 (61.8%) 7 (43.8%) 9 (56.3%) 0.710 Hormone receptor Either ER + or PgR+ Both ER and PgR+ 14 (35.9%) 25 (64.1%) 8 (50.0%) 8 (50.0%) 0.332 13 (38.2%) 21 (61.8%) 8 (50.0%) 8 (50.0%) 0.432 HER2 Negative Positive 38 (97.4%) 1 (2.6%) 15 (93.8%) 1 (6.3%) 0.507 33 (97.1%) 1 (2.9%) 15 (93.8%) 1 (6.3%) 0.578 Ki67 Low High 28 (71.8%) 11 (28.2%) 9 (56.3%) 7 (43.8%) 0.264 24 (70.6%) 10 (29.4%) 9 (56.3%) 7 (43.8%) 0.318 Endocrine therapy LH-RH agonist + TAM Other 11 (28.2%) 28 (71.8%) 6 (37.5%) 10 (62.5%) 0.498 5 (14.7%) 29 (85.3%) 6 (37.5%) 10 (62.5%) 0.070 Objective response rate Non-Responders Responders 11 (28.2%) 28 (71.8%) 7 (43.8%) 9 (56.3%) 0.264 11 (32.4%) 23 (67.6%) 7 (43.8%) 9 (56.3%) 0.434 Criteria for disease progression Increased of existing tumor Appearance of new metastasis - - - - - 27 (79.4%) 7 (20.6%) 8 (50.0%) 8 (50.0%) 0.034 HRBC: hormone receptor-positive breast cancer. ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen. During the follow-up period, breast cancer progression following first-line endocrine therapy was not observed in five patients (9.1%), classified as “responders” based on their ORR. All five patients took anastrozole because they were postmenopausal and were non-smokers. Conversely, breast cancer progression was observed during the primary endocrine treatment in 50 patients (90.9%). When the correlation between smoking and clinicopathological factors was examined in these patients, the tumors in smokers were significantly larger than that in non-smokers (p = 0.026), and ER-negative tumors were significantly more frequent in smokers than in non-smokers (p = 0.009), as examined for the whole above. Among them, it was significantly more frequent for smokers to be evaluated for disease progression because of the appearance of new metastases during endocrine therapy as first-line treatment (p = 0.034). No correlated clinicopathological factors other than smoking were found in the criteria for disease progression (Table 3 ). Furthermore, as the pack-year increased, new metastases tended to appear (pack-year ≤ 15: HR 1.929, p = 0.507; pack-year 15–30: HR 3.857, p = 0.223; pack-year > 30: HR 7.714, p = 0.028) (Table 4 ). Table 3 Correlation between clinicopathological features and criteria for disease progression. Parameters Criteria for disease progression p value Increased of existing tumor ( n = 35) Appearance of new metastasis ( n = 15) Age (years old) ≤ 60 > 60 16 (45.7%) 19 (54.3%) 6 (40.0%) 9 (60.0%) 0.709 Tumor size (mm) ≤ 50.0 > 50.0 20 (57.1%) 15 (42.9%) 10 (66.7%) 5 (33.3%) 0.529 Skin infiltration Negative Positive 11 (31.4%) 24 (68.6%) 6 (40.0%) 9 (60.0%) 0.558 Lymph node metastasis Negative Positive 4 (11.4%) 31 (88.6%) 1 (6.7%) 14 (93.3%) 0.607 The number of distant metastatic organs Single Multiple 18 (51.4%) 17 (48.6%) 8 (53.3%) 7 (46.7%) 0.902 Bone metastases No Yes 16 (45.7%) 19 (54.3%) 4 (26.7%) 11 (73.3%) 0.208 Lung metastases No Yes 14 (40.0%) 21 (60.0%) 7 (46.7%) 8 (53.3%) 0.662 Liver metastases No Yes 31 (88.6%) 4 (11.4%) 12 (80.0%) 3 (20.0%) 0.423 Estrogen receptor Negative Positive 1 (2.9%) 34 (97.1%) 1 (6.7%) 14 (93.3%) 0.529 Progesterone receptor Negative Positive 14 (40.0%) 21 (60.0%) 5 (33.3%) 10 (66.7%) 0.656 Hormone receptor Either ER + or PgR+ Both ER and PgR+ 15 (42.9%) 20 (57.1%) 6 (40.0%) 9 (60.0%) 0.851 HER2 Negative Positive 33 (94.3%) 2 (5.7%) 15 (100.0%) 0 (0.0%) 0.345 Ki67 Low High 24 (68.6%) 11 (31.4%) 9 (60.0%) 6 (40.0%) 0.558 Endocrine therapy LH-RH agonist + TAM Other 7 (20.0%) 28 (80.0%) 4 (26.7%) 11 (73.3%) 0.602 Objective response rate Non-Responders Responders 12 (34.3%) 23 (65.7%) 6 (40.0%) 9 (60.0%) 0.700 Smoker No Yes 27 (77.1%) 8 (22.9%) 7 (46.7%) 8 (53.3%) 0.034 ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen. Table 4 Univariate analysis with criteria for disease progression for smoking Smoking Criteria for disease progression Odd ratio 95% CI p value Increased of existing tumor / Appearance of new metastasis No-smoker 27 (79.4%) / 7 (20.6%) reference reference Pack-years of smoker ≤ 15 15–30 > 30 4 (66.7%) / 2 (33.3%) 2 (50.0%) / 2 (50.0%) 2 (33.3%) / 4 (66.7%) 1.929 3.857 7.714 0.291–12.766 0.459–32.424 1.165–51.064 0.507 0.223 0.028 smoker 8 (50.0%) / 8 (50.0%) 3.857 1.067–13.943 0.037 CI: confidence intervals. Effects Of Smoking On Prognosis First, the effects of smoking on prognosis were investigated in 55 patients with stage IV breast cancer who received endocrine therapy as first-line treatment. The log-rank test showed that smoking tended to shorten the PFS (p = 0.059, log-rank test) (Fig. 1 A). In the multivariate analysis of PFS, smoking was not an independent factor (HR: 1.448, p = 0.304), and only a high Ki was an independent factor (HR, 2.020; p = 0.044) (Table 5 ). Lymph node metastasis (hazard ratio [HR], 6.179; p = 0.035) and HER2 (HR; uncalculable, p = 0.021) were independent factors in the multivariate analysis of OS. Smoking was not an independent factor and the log-rank test showed no correlation with OS (p = 0.227, log-rank test) (Fig. 1 B). Table 5 Univariate and multivariate analysis with respect to PFS and OS in 55 stage 4 HRBC patients who received endocrine therapy. Progression-free survival Overall survival Univarite analysis Multivariate analysis Univarite analysis Multivariate analysis Parameters HRs 95% CI p value HRs 95% CI p value HRs 95% CI p value HRs 95% CI p value Age (years old) ≤ 60 vs > 60 0.584 0.319–1.067 0.080 0.735 0.373–1.464 0.377 0.794 0.325–1.942 0.609 Tumor size (mm) ≤ 50.0 vs > 50.0 1.122 0.608–2.038 0.707 1.893 0.782–4.708 0.156 Skin infiltration Negative vs Positive 0.904 0.498–1.699 0.746 2.280 0.830–8.010 0.115 Lymph node metastasis Negative vs Positive 1.661 0.714–4.853 0.259 4.269 0.879–76.873 0.078 6.179 1.115-118.538 0.035 The number of distant metastatic organs Single vs Multiple 1.537 0.848–2.791 0.155 2.171 0.888–5.608 0.089 2.200 0.737-6.700 0.155 Bone metastases No vs Yes 1.257 0.705–2.285 0.440 1.984 0.801–5.365 0.141 Lung metastases No vs Yes 0.638 0.357–1.160 0.138 0.619 0.254–1.548 0.296 Liver metastases No vs Yes 3.760 1.490–8.319 0.007 2.742 0.987–6.746 0.053 3.897 1.086–11.248 0.039 1.105 0.244–4.387 0.891 Estrogen receptor Negative vs Positive 0.426 0.128–2.641 0.301 0.651 0.132–11.801 0.697 Progesterone receptor Negative vs Positive 0.308 0.159–0.595 0.001 1.171 0.161–5.397 0.856 0.441 0.180–1.079 0.072 0.573 0.028–4.167 0.618 Hormone receptor Either ER + or PgR + vs Both ER and PgR+ 0.281 0.144–0.541 < 0.001 0.285 0.067–1.958 0.173 0.419 0.168–1.017 0.055 0.903 0.137–18.156 0.929 HER2 Negative vs Positive 3.170 0.505–10.907 0.182 - - 0.053 - - 0.021 Ki67 Low vs High 1.817 0.975–3.274 0.060 2.020 1.019–3.901 0.044 1.075 0.346–2.816 0.890 Endocrine therapy LH-RH agonist + TAM vs Other 0.901 0.464–1.886 0.770 1.302 0.475–4.562 0.630 Objective response rate Non-Responders vs Responders 0.275 0.146–0.529 < 0.001 0.613 0.275–1.345 0.222 0.397 0.159–1.007 0.052 0.504 0.159–1.642 0.251 Smoker No vs Yes 1.795 0.948–3.279 0.071 1.448 0.705–2.852 0.304 1.726 0.675–4.184 0.244 PFS: progression-free survival. OS: overall survival, HRBC: hormone receptor-positive breast cancer. HRs: hazard ratios. CI: confidence intervals. ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen. Next, the same studies were conducted on 50 patients with stage IV HRBC who experienced disease progression during primary endocrine therapy. In the log-rank test, smoking had no effect on the PFS or OS (PFS: p = 0.211, log-rank, Fig. 1 C; OS: p = 0.330, log-rank, Fig. 1 D). In the multivariate analysis of PFS, lung metastasis (HR, 0.433; p = 0.013), liver metastasis (HR, 2.550; p = 0.049), and treatment responsiveness (HR, 0.372, p = 0.012) were independent factors (Table 6 ). In contrast, in the multivariate analysis of OS, the only criterion for disease progression was an independent factor (HR, 3.762; p = 0.020). Table 6 Univariate and multivariate analysis with respect to PFS and OS in 50 stage 4 HRBC patients whose disease progresses during endocrine therapy. Progression-free survival Overall survival Univarite analysis Multivariate analysis Univarite analysis Multivariate analysis Parameters HRs 95% CI p value HRs 95% CI p value HRs 95% CI p value HRs 95% CI p value Age (years old) ≤ 60 vs > 60 0.741 0.405–1.353 0.327 0.915 0.374–2.239 0.843 Tumor size (mm) ≤ 50.0 vs > 50.0 1.076 0.582–1.960 0.812 1.799 0.743–4.472 0.191 Skin infiltration Negative vs Positive 0.821 0.453–1.538 0.528 2.106 0.770–7.370 0.155 Lymph node metastasis Negative vs Positive 0.890 0.380–2.601 0.811 3.278 0.673–59.065 0.167 The number of distant metastatic organs Single vs Multiple 1.280 0.708–2.315 0.411 1.940 0.795–5.003 0.146 Bone metastases No vs Yes 1.550 0.855–2.883 0.149 2.282 0.896–6.532 0.085 1.989 0.765–5.814 0.162 Lung metastases No vs Yes 0.449 0.245–0.831 0.011 0.433 0.225–0.838 0.013 0.528 0.211–1.339 0.174 Liver metastases No vs Yes 3.277 1.299–7.246 0.014 2.550 1.005–5.684 0.049 3.618 1.007–10.451 0.049 2.644 0.664–9.051 0.156 Estrogen receptor Negative vs Positive 0.488 0.146–3.029 0.376 0.700 0.141–12.697 0.744 Progesterone receptor Negative vs Positive 0.345 0.179–0.666 0.002 3.060 0.439–13.159 0.222 0.486 0.199–1.187 0.111 Hormone receptor Either ER + or PgR + vs Both ER and PgR+ 0.319 0.164–0.612 0.001 0.193 0.050–1.273 0.080 0.464 0.186–1.130 0.089 0.427 0.143–1.232 0.115 HER2 Negative vs Positive 2.795 0.445–9.614 0.227 - - 0.034 - - 0.082 Ki67 Low vs High 1.578 0.836–2.867 0.155 0.992 0.320–2.597 0.988 Endocrine therapy LH-RH agonist + TAM vs Other 1.088 0.560–2.279 0.810 1.441 0.525–5.052 0.501 Objective response rate Non-Responders vs Responders 0.325 0.173–0.624 0.001 0.372 0.176–0.799 0.012 0.437 0.174–1.107 0.080 0.588 0.217–1.652 0.305 Criteria for disease progression Increased of existing tumor vs Appearance of new metastasis 1.235 0.645–2.265 0.512 2.400 0.878–6.138 0.085 3.762 1.242–11.394 0.020 Smoker No vs Yes 1.476 0.780–2.694 0.224 1.555 0.608–3.767 0.343 PFS: progression-free survival. OS: overall survival, HRBC: hormone receptor-positive breast cancer. HRs: hazard ratios. CI: confidence intervals. ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen. Regarding the criteria for disease progression, the log-rank test also showed that the prognosis of patients with new metastatic lesions was not significantly different for PFS (p = 0.506, log-rank) (Fig. 2 A), but OS tended to be worse (p = 0.064, log-rank) ( Fig. 2 B). Discussion Smoking, which has been reported to be a poor prognostic factor in breast cancer treatment [ 4 – 7 , 9 ], was also associated with poor PFS in patients with first-line endocrine treatment in this study. This is because tobacco components have been reported to cause a more malignant biology [ 8 – 11 ]. Among these studies, this study is positioned as a rare report that smoking affects the progression of breast cancer during endocrine treatment. In a report examining the correlation between smoking and clinicopathological features in estrogen receptor-positive and HER2-negative early-stage breast cancers, most clinicopathological features were not found to correlate with smoking [ 13 ]. However, lymphovascular invasion was significantly more frequent in smokers than in non-smokers[ 13 ]. There are few reports examining the correlation between smoking and clinicopathological factors except for that report, but some studies have been conducted in vivo and in vitro. For example, it has been reported that nicotine, which is one of the main components of cigarette smoke, enhances both the cell proliferation [ 14 , 15 ] and the metastatic abilities of tumors [ 10 , 11 , 14 ]. There are also some reports that tobacco induces inflammation in the tumor microenvironment, which results in a metastatic environment[ 16 , 17 ]. These biological changes may have led to the results of this study. The appearance of new distant metastases during the course of treatment is also a poor prognostic factor [ 18 – 20 ]. In this study, smokers had a poor prognosis as smoking affected the progression of breast cancer. However, smoking affected PFS but not OS. In contrast, the criteria for disease progression in other studies were not based on the PFS but on a poor prognosis based on the OS, causing disparities in the results. The cause of this was not clear in this study. Chemotherapy may have been performed after primary endocrine therapy. It has been suggested that pharmacokinetic interactions with smoke components may affect the efficacy and toxicity of chemotherapy [ 21 ]. It has been reported that smoking affects the tumor immune microenvironment and temporarily affects the therapeutic effect of chemotherapy, which may be one of the causes [ 22 ]. One of the major limitations of this study was the small number of cases. Furthermore, the evaluation of smoking was not accurate because it was based on the results of an interview. Passive smoking is also a risk factor for breast cancer carcinogenesis [ 2 , 23 ]; therefore, passive smoking may also affect prognosis and alter the biology. However, the fact that smoking is not only involved in breast cancer carcinogenesis but also shows a difference in the progression of breast cancer suggests that it may also affect the biology. Although not an experiment with breast cancer cells, there are some reports that tobacco extract reduces E-cadherin in cancer cells [ 24 , 25 ]. It has been reported that the attenuation of E-cadherin expression is involved in breast cancer metastasis [ 26 ], which may be one of the causes. In the future, it will be necessary to investigate protein expression by immunohistochemical staining and changes in gene expression by reverse transcriptase-polymerase chain reaction using clinical specimens. Conclusions In stage IV HRBC, smoking increases the metastatic potential of breast cancer, suggesting that changes in its biology may lead to poor prognosis. Stage IV HRBC in heavy smokers should be treated with caution because of the emergence of distant metastases. Abbreviations ANA anastrozole cCR clinical complete response CI confidence interval cPD clinical progressive disease cPR clinical partial response cSD clinical stable disease ER estrogen receptor HER2 human epidermal growth factor receptor 2 HR hazard ratio HRBC hormone receptor-positive breast cancer LH-RH luteinizing hormone-releasing hormone ORR objective response rate OS overall survival PFS progression-free survival PgR progesterone receptor TAM tamoxifen. Declarations Ethics approval and consent to participate A written informed consent to participate in the study was obtained from each subject in accordance with the declaration of Helsinki principles. Each patient or the patient’s family was fully informed of the investigational nature of this study and provided their written, informed consent. The study protocol was approved by the Ethics Committee of Osaka City University (approve number #926). Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available due but are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was supported in part by Grants-in-Aid for Scientific Research (KAKENHI , Nos. 17K10559, 19K18067 and 20K08938) from the Ministry of Education, Science, Sports, Culture and Technology of Japan. Authors’ contributions KT participated in the design of the study and drafted the manuscript. SK participated in the design of the study and manuscript editing. AY, NI, WG, YA, YT, TM and KO helped with study data collection and manuscript preparation. MS and MO conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors have read and approved the final manuscript. Acknowledgements We thank Tomomi Okawa (Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine) for helpful advice regarding data management. Author’s information 1 Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. 2 Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. References Hortobagyi GN: Treatment of breast cancer . N Engl J Med 1998, 339 :974–984. Dossus L, Boutron-Ruault MC, Kaaks R, Gram IT, Vilier A, Fervers B, Manjer J, Tjonneland A, Olsen A, Overvad K, et al: Active and passive cigarette smoking and breast cancer risk: results from the EPIC cohort . Int J Cancer 2014, 134 :1871–1888. 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Wang K, Li F, Zhang X, Li Z, Li H: Smoking increases risks of all-cause and breast cancer specific mortality in breast cancer individuals: a dose-response meta-analysis of prospective cohort studies involving 39725 breast cancer cases . Oncotarget 2016, 7 :83134–83147. Hecht SS: Tobacco smoke carcinogens and breast cancer . Environ Mol Mutagen 2002, 39 :119–126. Perera FP, Estabrook A, Hewer A, Channing K, Rundle A, Mooney LA, Whyatt R, Phillips DH: Carcinogen-DNA adducts in human breast tissue . Cancer Epidemiol Biomarkers Prev 1995, 4 :233–238. Di Cello F, Flowers VL, Li H, Vecchio-Pagan B, Gordon B, Harbom K, Shin J, Beaty R, Wang W, Brayton C, et al: Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells . Mol Cancer 2013, 12 :90. Singh S, Pillai S, Chellappan S: Nicotinic acetylcholine receptor signaling in tumor growth and metastasis . J Oncol 2011, 2011 :456743. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer 2009, 45 :228–247. Goldvaser H, Gal O, Rizel S, Hendler D, Neiman V, Shochat T, Sulkes A, Brenner B, Yerushalmi R: The association between smoking and breast cancer characteristics and outcome . BMC Cancer 2017, 17 :624. Nishioka T, Kim HS, Luo LY, Huang Y, Guo J, Chen CY: Sensitization of epithelial growth factor receptors by nicotine exposure to promote breast cancer cell growth . Breast Cancer Res 2011, 13 :R113. Chen CS, Lee CH, Hsieh CD, Ho CT, Pan MH, Huang CS, Tu SH, Wang YJ, Chen LC, Chang YJ, et al: Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins . Breast Cancer Res Treat 2011, 125 :73–87. Bennett JM, Glaser R, Andridge RR, Peng J, Malarkey WB, Kiecolt-Glaser JK: Long lasting effects of smoking: breast cancer survivors' inflammatory responses to acute stress differ by smoking history . Psychoneuroendocrinology 2013, 38 :179–187. Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation . Nature 2008, 454 :436–444. Twelves C, Cortes J, Kaufman PA, Yelle L, Awada A, Binder TA, Olivo M, Song J, O'Shaughnessy JA, Jove M, Perez EA: "New" metastases are associated with a poorer prognosis than growth of pre-existing metastases in patients with metastatic breast cancer treated with chemotherapy . Breast Cancer Res 2015, 17 :150. Litiere S, de Vries EGE, Seymour L, Sargent D, Shankar L, Bogaerts J, Committee R: The components of progression as explanatory variables for overall survival in the Response Evaluation Criteria in Solid Tumours 1.1 database . Eur J Cancer 2014, 50 :1847–1853. Kashiwagi S, Tsujio G, Asano Y, Goto W, Takada K, Takahashi K, Morisaki T, Fujita H, Takashima T, Tomita S, et al: Study on the progression types of cancer in patients with breast cancer undergoing eribulin chemotherapy and tumor microenvironment . J Transl Med 2018, 16 :54. Condoluci A, Mazzara C, Zoccoli A, Pezzuto A, Tonini G: Impact of smoking on lung cancer treatment effectiveness: a review . Future Oncol 2016, 12 :2149–2161. Takada K, Kashiwagi S, Asano Y, Goto W, Takahashi K, Fujita H, Takashima T, Tomita S, Hirakawa K, Ohira M: Clinical verification of the relationship between smoking and the immune microenvironment of breast cancer . J Transl Med 2019, 17 :13. Macacu A, Autier P, Boniol M, Boyle P: Active and passive smoking and risk of breast cancer: a meta-analysis . Breast Cancer Res Treat 2015, 154 :213–224. Forteza RM, Casalino-Matsuda SM, Falcon NS, Valencia Gattas M, Monzon ME: Hyaluronan and layilin mediate loss of airway epithelial barrier function induced by cigarette smoke by decreasing E-cadherin . J Biol Chem 2012, 287 :42288–42298. Oldenburger A, Poppinga WJ, Kos F, de Bruin HG, Rijks WF, Heijink IH, Timens W, Meurs H, Maarsingh H, Schmidt M: A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smoke . Am J Physiol Cell Physiol 2014, 306 :C585-597. Goto W, Kashiwagi S, Asano Y, Takada K, Takahashi K, Hatano T, Takashima T, Tomita S, Motomura H, Ohsawa M, et al: Circulating tumor cell clusters-associated gene plakoglobin is a significant prognostic predictor in patients with breast cancer . Biomark Res 2017, 5 :19. 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-1365423","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":88918020,"identity":"bf0413d6-caf5-490b-aa6d-2600d73164c0","order_by":0,"name":"Koji Takada","email":"","orcid":"","institution":"Osaka City University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Takada","suffix":""},{"id":88918021,"identity":"07fa6499-141a-4ba7-b497-41de31ddf65f","order_by":1,"name":"Shinichiro Kashiwagi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYLCCDwcY5PgZGBuQhHjw62CccYDBWLKBFC3MPAcYEjccINZN8rObt0nznLFJ3HwjufExD4ONvDkD78EHDDJ3cGoxuHOsTHLOjTTjbTcSm415GNIMdzbwJRsw8DzDrUUix9jgzYfDstvOHGyTzmE4nGBwgMdMgoHnMG6HzQBq4fnwn3Fzz8H231At5j/waWG4kWP4kOfGAcUN7I1tzDBbGPBpAfql8OGMM8nGEscbm6X/GKQZbjjMYyyRgMcvwBDbcODDMTs5/mb2hx9nVNjIGxzvMfzwsQd3iDFIMBggWwrEzECc2HOAWC1w8AOPllEwCkbBKBhpAADa91llfje/kQAAAABJRU5ErkJggg==","orcid":"","institution":"Osaka City University Graduate School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Shinichiro","middleName":"","lastName":"Kashiwagi","suffix":""},{"id":88918022,"identity":"f7084e43-1ebe-44a7-b761-2a29c45468bb","order_by":2,"name":"Akimichi Yabumoto","email":"","orcid":"","institution":"Osaka City University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Akimichi","middleName":"","lastName":"Yabumoto","suffix":""},{"id":88918023,"identity":"b4d7d313-6e06-493c-97ab-fd904e12fe82","order_by":3,"name":"Nozomi Iimori","email":"","orcid":"","institution":"Osaka City University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nozomi","middleName":"","lastName":"Iimori","suffix":""},{"id":88918024,"identity":"e8915729-e86b-4714-8d3e-69d15e1b016f","order_by":4,"name":"Wataru Goto","email":"","orcid":"","institution":"Osaka City University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wataru","middleName":"","lastName":"Goto","suffix":""},{"id":88918025,"identity":"cac7de5c-07b3-4ac2-9568-617b707e8015","order_by":5,"name":"Yuka Asano","email":"","orcid":"","institution":"Osaka City University Graduate School of 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Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kana","middleName":"","lastName":"Ogisawa","suffix":""},{"id":88918029,"identity":"c2c0c74e-5faa-43f0-bdf5-a01004735361","order_by":9,"name":"Masatsune Shibutani","email":"","orcid":"","institution":"Osaka City University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masatsune","middleName":"","lastName":"Shibutani","suffix":""},{"id":88918030,"identity":"1ea70514-00e6-4beb-8071-6af5b5ef5704","order_by":10,"name":"Masaichi Ohira","email":"","orcid":"","institution":"Osaka City University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masaichi","middleName":"","lastName":"Ohira","suffix":""}],"badges":[],"createdAt":"2022-02-16 11:44:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1365423/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1365423/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":19082554,"identity":"dfc53180-25bd-4644-9ef1-37c18a499183","added_by":"auto","created_at":"2022-03-10 15:52:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":27682,"visible":true,"origin":"","legend":"\u003cp\u003eThe effects of smoking on prognosis were investigated in 55 patients with stage IV hormone receptor-positive breast cancer who received endocrine therapy as first-line treatment. The log-rank test showed that smoking tended to shorten the PFS (p=0.059, log-rank test) (A). But no correlation with OS (p=0.227, log-rank test) (B). In addition, the same studies were conducted on 50 patients with stage IV hormone receptor-positive breast cancer who experienced disease progression during primary endocrine therapy. In the log-rank test, smoking had no effect on the PFS or OS (PFS p=0.211, log-rank: C, OS p=0.330, log-rank: D).\u003c/p\u003e","description":"","filename":"OnlineFig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-1365423/v1/4a468cda51fee0d4343e879c.png"},{"id":19082553,"identity":"a7daa850-4857-4313-a2be-11e242550328","added_by":"auto","created_at":"2022-03-10 15:52:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":17191,"visible":true,"origin":"","legend":"\u003cp\u003eRegarding the criteria for disease progression, the log-rank test also showed that the prognosis of patients with new metastatic lesions was not significantly different for PFS (p=0.506, log-rank) (A), but OS tended to be worse (p=0.064, log-rank) (B).\u003c/p\u003e","description":"","filename":"OnlineFig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-1365423/v1/864e312371e288ad301515f0.png"},{"id":19724902,"identity":"882a7d06-a723-4b6c-bae5-3328e0334405","added_by":"auto","created_at":"2022-03-29 10:29:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1149242,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1365423/v1/cb5dc453-f1be-499d-a131-2c26cbfa0ef6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Smoking on Endocrine Therapy for Stage IV Hormone Receptor Positive Breast Cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eOne of the important aspects of breast cancer treatment strategies for distant metastases is prolonging survival while maintaining a good quality of life. Therefore, in the past, the treatment of non-life-threatening hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer with distant metastases was often initiated with endocrine therapy using the Hortobagyi algorithm [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, breast cancer may progress rapidly even with endocrine therapy.\u003c/p\u003e \u003cp\u003eSmoking is recognized as a carcinogenic risk factor for breast cancer [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Additionally, it has been reported to worsen breast cancer [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] as the tobacco components directly reach mammary gland tissue, causing smoking-related DNA damage and biological changes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These biological changes have led to more malignant tumors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, we hypothesized that smoking may have a distinct course other than the therapeutic effect in patients with stage IV hormone receptor-positive breast cancer (HRBC) who received endocrine therapy as the first-line treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient background\u003c/h2\u003e \u003cp\u003eFrom November 2007 to September 2017, 56 patients diagnosed with stage IV HRBC started endocrine therapy as the first-line treatment at Osaka City University Hospital. Before treatment, the period and amount of smoking were confirmed by interviewing the patients, and each pack-year was recorded. However, one patient was excluded from this study because of the unknown smoking history details. All patients underwent biopsy before treatment and were histologically diagnosed with breast cancer. In addition, the expression of the estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was evaluated through immunohistochemical staining of the biopsy tissue. Breast cancer with positive ER and/or PgR expression was defined as HRBC. Breast cancer staging was evaluated using ultrasonography, computed tomography, and bone scintigraphy. Subsequently, physical and imaging examinations were performed as needed in the outpatient department. Therapeutic effects were evaluated according to the Response Evaluation Criteria in Solid Tumors [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In this study, patients with clinical partial and complete responses based on the objective response rate were defined as \u0026ldquo;responders.\u0026rdquo; Meanwhile, those with clinical stable and progressive diseases were as classified as \u0026ldquo;non-responders\u0026rdquo; in objective response rate (ORR). The median follow-up period was 1539 days (range, 9\u0026ndash;4479 days).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using the JMP software package (SAS, Tokyo, Japan). The relationship between each factor was examined using a χ2 test. The progression-free survival (PFS) and overall survival (OS) were compared using the Kaplan-Meier method and log-rank test. Hazard ratios (HRs) and 95% confidence intervals were calculated using the Cox proportional hazards model. Multivariate analysis was performed using the Cox regression model. Statistical significance was defined as a p-value less than 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eClinicopathological features\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the clinicopathological features of the 55 patients with stage IV HRBC who received endocrine therapy as first-line treatment. The median age of the patients was 63 (range, 38\u0026ndash;89) years. The median tumor diameter was 40.7 mm (range, 9.2\u0026ndash;146.3 mm), and 37 patients (67.3%) had skin infiltration. The absence of swelling regional lymph nodes was observed in only seven patients (12.7%). There were several cases of bone (34 cases, 61.8%) and lung metastases (31 cases, 56.4%). Twenty-five patients (45.5%) had metastasis to multiple organs. All patients with bone metastases received zoledronic acid or denosumab in combination with endocrine therapy. Fifty-three patients (96.4%) had ER-positive breast cancer, while 35 (63.6%) had PgR-positive breast cancer. Furthermore, 33 patients (60.0%) had both ER-and PgR-positive breast cancer. There were two patients with HER2-positive breast cancers (3.6%), but they did not receive anti-HER2 molecule-targeted drugs, such as trastuzumab. Ki67 was highly expressed in 18 patients (32.7%). Letrozole was the most commonly used primary endocrine therapy in 31 cases (56.4%). All 11 premenopausal patients (20.0%) were treated with luteinizing hormone-releasing hormone agonists and tamoxifen. Based on the ORR, 37 patients (67.3%) were evaluated as \u0026ldquo;responders\u0026rdquo;. Regarding smoking, 39 patients (70.9%) were nonsmokers. The median pack-years of the 16 smokers was 21.0 (range; 1.5\u0026ndash;48.0).\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 features of HRBC patients with distant metastasis who received endocrine therapy as the primary treatment.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of all patients (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;55) (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNumber of patients whose disease progresses\u003c/p\u003e \u003cp\u003eduring endocrine therapy (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;50) (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years old)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (38\u0026ndash;89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (38\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.7 (9.2\u0026ndash;146.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.5 (11.8\u0026ndash;146.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin infiltration\u003c/p\u003e \u003cp\u003eNegative / Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (32.7%) / 37 (67.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (34.0%) / 33 (66.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node metastasis\u003c/p\u003e \u003cp\u003eNegative / Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (12.7%) / 48 (87.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (10.0%) / 45 (90.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe number of distant metastatic organs\u003c/p\u003e \u003cp\u003e1 / 2 / 3 / 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (54.5%) / 17 (30.9%) / 7 (12.7%) / 1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (52.0%) / 16 (32.0%) / 7 (14.0%) / 1 (2.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite of metastases\u003c/p\u003e \u003cp\u003eBone / Lung / Liver /\u003c/p\u003e \u003cp\u003eSkin / Brain / Distant lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (61.8%) / 31 (56.4%) / 7 (12.7%) /\u003c/p\u003e \u003cp\u003e1 (1.8%) / 1 (1.8%) / 15 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (60.0%) / 29 (58.0%) / 7 (14.0%) /\u003c/p\u003e \u003cp\u003e1 (2.0%) / 1 (2.0%) / 15 (30.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone receptor\u003c/p\u003e \u003cp\u003eBoth ER and PgR+ / only ER+ / only PgR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (60.0%) / 20 (36.4%) / 2 (3.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (58.0%) / 19 (38.0%) / 2 (4.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003c/p\u003e \u003cp\u003eNegative / Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (96.4%) / 2 (3.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (96.0%) / 2 (4.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi67\u003c/p\u003e \u003cp\u003eLow / High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (67.3%) / 18 (32.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (66.0%) / 17 (34.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine therapy\u003c/p\u003e \u003cp\u003eLET / ANA / LH-RH agonist\u0026thinsp;+\u0026thinsp;TAM / EXE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (56.4%) / 12 (21.8%) / 11 (20.0%) / 1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (62.0%) / 7 (14.0%) / 11 (22.0%) / 1 (2.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response rate\u003c/p\u003e \u003cp\u003eNon-Responders / Responders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (32.7%) / 37 (67.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (36.0%) / 32 (64.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCriteria for disease progression\u003c/p\u003e \u003cp\u003eNo disease progression /\u003c/p\u003e \u003cp\u003eIncreased of existing tumor /\u003c/p\u003e \u003cp\u003eAppearance of new metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (9.1%) /\u003c/p\u003e \u003cp\u003e35 (63.6%) /\u003c/p\u003e \u003cp\u003e15 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (70.0%) /\u003c/p\u003e \u003cp\u003e15 (30.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoker\u003c/p\u003e \u003cp\u003eNo / Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (70.9%) / 16 (29.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (68.0%) / 16 (32.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePack-years of smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.0 (1.5\u0026ndash;48.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.0 (1.5\u0026ndash;48.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eHRBC: hormone receptor-positive breast cancer. ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LET: letrozole. ANA: anastrozole. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen. EXE: exemestane.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch2\u003eCorrelations Between The Clinicopathological Features And Smoking\u003c/h2\u003e\n\u003cp\u003eThe correlation between the patients\u0026rsquo; clinicopathological features and smoking status was also examined (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The smokers were significantly younger than the non-smokers (p\u0026thinsp;=\u0026thinsp;0.029). Breast cancer in smokers had a significantly larger tumor diameter (p\u0026thinsp;=\u0026thinsp;0.017) and significantly less frequent ER positivity (p\u0026thinsp;=\u0026thinsp;0.005) than that in non-smokers.\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\u003eCorrelation between clinicopathological features and smoke in stage 4 HRBC patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003ePatients whose disease progresses\u003c/p\u003e \u003cp\u003eduring endocrine therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-smoker\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSmoker\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNon-smoker\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSmoker\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years old)\u003c/p\u003e \u003cp\u003e\u0026le; 60\u003c/p\u003e \u003cp\u003e\u0026gt; 60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (30.8%)\u003c/p\u003e \u003cp\u003e27 (69.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (35.3%)\u003c/p\u003e \u003cp\u003e22 (64.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (mm)\u003c/p\u003e \u003cp\u003e\u0026le; 50.0\u003c/p\u003e \u003cp\u003e\u0026gt; 50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (71.8%)\u003c/p\u003e \u003cp\u003e11 (28.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 (70.6%)\u003c/p\u003e \u003cp\u003e10 (29.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin infiltration\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (38.5%)\u003c/p\u003e \u003cp\u003e24 (61.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (18.8%)\u003c/p\u003e \u003cp\u003e13 (81.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (41.2%)\u003c/p\u003e \u003cp\u003e20 (58.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (18.8%)\u003c/p\u003e \u003cp\u003e13 (81.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node metastasis\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (15.4%)\u003c/p\u003e \u003cp\u003e33 (84.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (6.3%)\u003c/p\u003e \u003cp\u003e15 (93.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.356\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (11.8%)\u003c/p\u003e \u003cp\u003e30 (88.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (6.3%)\u003c/p\u003e \u003cp\u003e15 (93.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.544\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe number of distant metastatic organs\u003c/p\u003e \u003cp\u003eSingle\u003c/p\u003e \u003cp\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (56.4%)\u003c/p\u003e \u003cp\u003e17 (43.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (52.9%)\u003c/p\u003e \u003cp\u003e16 (47.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.846\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone metastases\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (33.3%)\u003c/p\u003e \u003cp\u003e26 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (35.3%)\u003c/p\u003e \u003cp\u003e22 (64.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.322\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung metastases\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (48.7%)\u003c/p\u003e \u003cp\u003e20 (51.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (31.3%)\u003c/p\u003e \u003cp\u003e11 (68.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (47.1%)\u003c/p\u003e \u003cp\u003e18 (52.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5 (31.3%)\u003c/p\u003e \u003cp\u003e11 (68.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.291\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver metastases\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (92.3%)\u003c/p\u003e \u003cp\u003e3 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (75.0%)\u003c/p\u003e \u003cp\u003e4 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31 (91.2%)\u003c/p\u003e \u003cp\u003e3 (8.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 (75.0%)\u003c/p\u003e \u003cp\u003e4 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.124\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstrogen receptor\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003cp\u003e39 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (18.8%)\u003c/p\u003e \u003cp\u003e13 (81.3%)\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\u003e0 (0.0%)\u003c/p\u003e \u003cp\u003e34 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (18.8%)\u003c/p\u003e \u003cp\u003e13 (81.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgesterone receptor\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (35.9%)\u003c/p\u003e \u003cp\u003e25 (64.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (43.8%)\u003c/p\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.586\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (38.2%)\u003c/p\u003e \u003cp\u003e21 (61.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7 (43.8%)\u003c/p\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.710\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone receptor\u003c/p\u003e \u003cp\u003eEither ER\u0026thinsp;+\u0026thinsp;or PgR+\u003c/p\u003e \u003cp\u003eBoth ER and PgR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (35.9%)\u003c/p\u003e \u003cp\u003e25 (64.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.332\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (38.2%)\u003c/p\u003e \u003cp\u003e21 (61.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.432\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (97.4%)\u003c/p\u003e \u003cp\u003e1 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (93.8%)\u003c/p\u003e \u003cp\u003e1 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.507\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33 (97.1%)\u003c/p\u003e \u003cp\u003e1 (2.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15 (93.8%)\u003c/p\u003e \u003cp\u003e1 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.578\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi67\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (71.8%)\u003c/p\u003e \u003cp\u003e11 (28.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003cp\u003e7 (43.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 (70.6%)\u003c/p\u003e \u003cp\u003e10 (29.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003cp\u003e7 (43.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.318\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine therapy\u003c/p\u003e \u003cp\u003eLH-RH agonist\u0026thinsp;+\u0026thinsp;TAM\u003c/p\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (28.2%)\u003c/p\u003e \u003cp\u003e28 (71.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.498\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (14.7%)\u003c/p\u003e \u003cp\u003e29 (85.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response rate\u003c/p\u003e \u003cp\u003eNon-Responders\u003c/p\u003e \u003cp\u003eResponders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (28.2%)\u003c/p\u003e \u003cp\u003e28 (71.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (43.8%)\u003c/p\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (32.4%)\u003c/p\u003e \u003cp\u003e23 (67.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7 (43.8%)\u003c/p\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.434\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCriteria for disease progression\u003c/p\u003e \u003cp\u003eIncreased of existing tumor\u003c/p\u003e \u003cp\u003eAppearance of new metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 (79.4%)\u003c/p\u003e \u003cp\u003e7 (20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003cp\u003e8 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eHRBC: hormone receptor-positive breast cancer. ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDuring the follow-up period, breast cancer progression following first-line endocrine therapy was not observed in five patients (9.1%), classified as \u0026ldquo;responders\u0026rdquo; based on their ORR. All five patients took anastrozole because they were postmenopausal and were non-smokers. Conversely, breast cancer progression was observed during the primary endocrine treatment in 50 patients (90.9%). When the correlation between smoking and clinicopathological factors was examined in these patients, the tumors in smokers were significantly larger than that in non-smokers (p\u0026thinsp;=\u0026thinsp;0.026), and ER-negative tumors were significantly more frequent in smokers than in non-smokers (p\u0026thinsp;=\u0026thinsp;0.009), as examined for the whole above. Among them, it was significantly more frequent for smokers to be evaluated for disease progression because of the appearance of new metastases during endocrine therapy as first-line treatment (p\u0026thinsp;=\u0026thinsp;0.034). No correlated clinicopathological factors other than smoking were found in the criteria for disease progression (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Furthermore, as the pack-year increased, new metastases tended to appear (pack-year\u0026thinsp;\u0026le;\u0026thinsp;15: HR 1.929, p\u0026thinsp;=\u0026thinsp;0.507; pack-year 15\u0026ndash;30: HR 3.857, p\u0026thinsp;=\u0026thinsp;0.223; pack-year\u0026thinsp;\u0026gt;\u0026thinsp;30: HR 7.714, p\u0026thinsp;=\u0026thinsp;0.028) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\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\u003eCorrelation between clinicopathological features and criteria for disease progression.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eCriteria for disease progression\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIncreased of existing tumor\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAppearance of new metastasis\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years old)\u003c/p\u003e \u003cp\u003e\u0026le; 60\u003c/p\u003e \u003cp\u003e\u0026gt; 60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (45.7%)\u003c/p\u003e \u003cp\u003e19 (54.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (40.0%)\u003c/p\u003e \u003cp\u003e9 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.709\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (mm)\u003c/p\u003e \u003cp\u003e\u0026le; 50.0\u003c/p\u003e \u003cp\u003e\u0026gt; 50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (57.1%)\u003c/p\u003e \u003cp\u003e15 (42.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (66.7%)\u003c/p\u003e \u003cp\u003e5 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.529\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin infiltration\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (31.4%)\u003c/p\u003e \u003cp\u003e24 (68.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (40.0%)\u003c/p\u003e \u003cp\u003e9 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node metastasis\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11.4%)\u003c/p\u003e \u003cp\u003e31 (88.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (6.7%)\u003c/p\u003e \u003cp\u003e14 (93.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.607\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe number of distant metastatic organs\u003c/p\u003e \u003cp\u003eSingle\u003c/p\u003e \u003cp\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (51.4%)\u003c/p\u003e \u003cp\u003e17 (48.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (53.3%)\u003c/p\u003e \u003cp\u003e7 (46.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.902\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone metastases\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (45.7%)\u003c/p\u003e \u003cp\u003e19 (54.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (26.7%)\u003c/p\u003e \u003cp\u003e11 (73.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung metastases\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (40.0%)\u003c/p\u003e \u003cp\u003e21 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (46.7%)\u003c/p\u003e \u003cp\u003e8 (53.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.662\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver metastases\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (88.6%)\u003c/p\u003e \u003cp\u003e4 (11.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (80.0%)\u003c/p\u003e \u003cp\u003e3 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstrogen receptor\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.9%)\u003c/p\u003e \u003cp\u003e34 (97.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (6.7%)\u003c/p\u003e \u003cp\u003e14 (93.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.529\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgesterone receptor\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (40.0%)\u003c/p\u003e \u003cp\u003e21 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (33.3%)\u003c/p\u003e \u003cp\u003e10 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.656\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone receptor\u003c/p\u003e \u003cp\u003eEither ER\u0026thinsp;+\u0026thinsp;or PgR+\u003c/p\u003e \u003cp\u003eBoth ER and PgR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (42.9%)\u003c/p\u003e \u003cp\u003e20 (57.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (40.0%)\u003c/p\u003e \u003cp\u003e9 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.851\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (94.3%)\u003c/p\u003e \u003cp\u003e2 (5.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (100.0%)\u003c/p\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.345\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi67\u003c/p\u003e \u003cp\u003eLow\u003c/p\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (68.6%)\u003c/p\u003e \u003cp\u003e11 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (60.0%)\u003c/p\u003e \u003cp\u003e6 (40.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine therapy\u003c/p\u003e \u003cp\u003eLH-RH agonist\u0026thinsp;+\u0026thinsp;TAM\u003c/p\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (20.0%)\u003c/p\u003e \u003cp\u003e28 (80.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (26.7%)\u003c/p\u003e \u003cp\u003e11 (73.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.602\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response rate\u003c/p\u003e \u003cp\u003eNon-Responders\u003c/p\u003e \u003cp\u003eResponders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (34.3%)\u003c/p\u003e \u003cp\u003e23 (65.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (40.0%)\u003c/p\u003e \u003cp\u003e9 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.700\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoker\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (77.1%)\u003c/p\u003e \u003cp\u003e8 (22.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (46.7%)\u003c/p\u003e \u003cp\u003e8 (53.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\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\u003eUnivariate analysis with criteria for disease progression for smoking\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCriteria for disease progression\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOdd ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIncreased of existing tumor / Appearance of new metastasis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27 (79.4%) / 7 (20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ereference\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\u003ePack-years of smoker\u003c/p\u003e \u003cp\u003e\u0026le; 15\u003c/p\u003e \u003cp\u003e15\u0026ndash;30\u003c/p\u003e \u003cp\u003e\u0026gt; 30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (66.7%) / 2 (33.3%)\u003c/p\u003e \u003cp\u003e2 (50.0%) / 2 (50.0%)\u003c/p\u003e \u003cp\u003e2 (33.3%) / 4 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.929\u003c/p\u003e \u003cp\u003e3.857\u003c/p\u003e \u003cp\u003e7.714\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.291\u0026ndash;12.766\u003c/p\u003e \u003cp\u003e0.459\u0026ndash;32.424\u003c/p\u003e \u003cp\u003e1.165\u0026ndash;51.064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.507\u003c/p\u003e \u003cp\u003e0.223\u003c/p\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esmoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (50.0%) / 8 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.857\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.067\u0026ndash;13.943\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCI: confidence intervals.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch2\u003eEffects Of Smoking On Prognosis\u003c/h2\u003e\n\u003cp\u003eFirst, the effects of smoking on prognosis were investigated in 55 patients with stage IV breast cancer who received endocrine therapy as first-line treatment. The log-rank test showed that smoking tended to shorten the PFS (p\u0026thinsp;=\u0026thinsp;0.059, log-rank test) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). In the multivariate analysis of PFS, smoking was not an independent factor (HR: 1.448, p\u0026thinsp;=\u0026thinsp;0.304), and only a high Ki was an independent factor (HR, 2.020; p\u0026thinsp;=\u0026thinsp;0.044) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Lymph node metastasis (hazard ratio [HR], 6.179; p\u0026thinsp;=\u0026thinsp;0.035) and HER2 (HR; uncalculable, p\u0026thinsp;=\u0026thinsp;0.021) were independent factors in the multivariate analysis of OS. Smoking was not an independent factor and the log-rank test showed no correlation with OS (p\u0026thinsp;=\u0026thinsp;0.227, log-rank test) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\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\u003eUnivariate and multivariate analysis with respect to PFS and OS in 55 stage 4 HRBC patients who received endocrine therapy.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"16\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c8\" namest=\"c2\"\u003e \u003cp\u003eProgression-free survival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c16\" namest=\"c10\"\u003e \u003cp\u003eOverall survival\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\u003eUnivarite analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e \u003cp\u003eUnivarite analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHRs\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\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHRs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHRs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eHRs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years old)\u003c/p\u003e \u003cp\u003e\u0026le; 60 vs\u0026thinsp;\u0026gt;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.584\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.319\u0026ndash;1.067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.735\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.373\u0026ndash;1.464\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.377\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.794\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.325\u0026ndash;1.942\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.609\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (mm)\u003c/p\u003e \u003cp\u003e\u0026le; 50.0 vs\u0026thinsp;\u0026gt;\u0026thinsp;50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.608\u0026ndash;2.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.707\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.782\u0026ndash;4.708\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin infiltration\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.904\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.498\u0026ndash;1.699\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.746\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.830\u0026ndash;8.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node metastasis\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.661\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.714\u0026ndash;4.853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.259\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.269\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.879\u0026ndash;76.873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e6.179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.115-118.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe number of distant metastatic organs\u003c/p\u003e \u003cp\u003eSingle vs Multiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.537\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.848\u0026ndash;2.791\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.155\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.171\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.888\u0026ndash;5.608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.737-6.700\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone metastases\u003c/p\u003e \u003cp\u003eNo vs Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.257\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.705\u0026ndash;2.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.440\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.984\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.801\u0026ndash;5.365\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung metastases\u003c/p\u003e \u003cp\u003eNo vs Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.638\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.357\u0026ndash;1.160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.138\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.619\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.254\u0026ndash;1.548\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.296\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver metastases\u003c/p\u003e \u003cp\u003eNo vs Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.760\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.490\u0026ndash;8.319\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.742\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.987\u0026ndash;6.746\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.897\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.086\u0026ndash;11.248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.244\u0026ndash;4.387\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.891\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstrogen receptor\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.426\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.128\u0026ndash;2.641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.301\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.651\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.132\u0026ndash;11.801\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgesterone receptor\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.308\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.159\u0026ndash;0.595\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.171\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.161\u0026ndash;5.397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.856\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.180\u0026ndash;1.079\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.028\u0026ndash;4.167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.618\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone receptor\u003c/p\u003e \u003cp\u003eEither ER\u0026thinsp;+\u0026thinsp;or PgR\u0026thinsp;+\u0026thinsp;vs Both ER and PgR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.281\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.144\u0026ndash;0.541\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.067\u0026ndash;1.958\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.168\u0026ndash;1.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.903\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.137\u0026ndash;18.156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.929\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.505\u0026ndash;10.907\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.182\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi67\u003c/p\u003e \u003cp\u003eLow vs High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.817\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.975\u0026ndash;3.274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.019\u0026ndash;3.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.346\u0026ndash;2.816\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.890\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine therapy\u003c/p\u003e \u003cp\u003eLH-RH agonist\u0026thinsp;+\u0026thinsp;TAM vs Other\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.464\u0026ndash;1.886\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.770\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.475\u0026ndash;4.562\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.630\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response rate\u003c/p\u003e \u003cp\u003eNon-Responders vs Responders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.275\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.146\u0026ndash;0.529\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.613\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.275\u0026ndash;1.345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.222\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.159\u0026ndash;1.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.504\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.159\u0026ndash;1.642\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.251\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoker\u003c/p\u003e \u003cp\u003eNo vs Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.948\u0026ndash;3.279\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.448\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.705\u0026ndash;2.852\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.304\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.726\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.675\u0026ndash;4.184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"16\"\u003ePFS: progression-free survival. OS: overall survival, HRBC: hormone receptor-positive breast cancer. HRs: hazard ratios. CI: confidence intervals. ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNext, the same studies were conducted on 50 patients with stage IV HRBC who experienced disease progression during primary endocrine therapy. In the log-rank test, smoking had no effect on the PFS or OS (PFS: p\u0026thinsp;=\u0026thinsp;0.211, log-rank, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC; OS: p\u0026thinsp;=\u0026thinsp;0.330, log-rank, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). In the multivariate analysis of PFS, lung metastasis (HR, 0.433; p\u0026thinsp;=\u0026thinsp;0.013), liver metastasis (HR, 2.550; p\u0026thinsp;=\u0026thinsp;0.049), and treatment responsiveness (HR, 0.372, p\u0026thinsp;=\u0026thinsp;0.012) were independent factors (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). In contrast, in the multivariate analysis of OS, the only criterion for disease progression was an independent factor (HR, 3.762; p\u0026thinsp;=\u0026thinsp;0.020).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analysis with respect to PFS and OS in 50 stage 4 HRBC patients whose disease progresses during endocrine therapy.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"16\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c8\" namest=\"c2\"\u003e \u003cp\u003eProgression-free survival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c16\" namest=\"c10\"\u003e \u003cp\u003eOverall survival\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\u003eUnivarite analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e \u003cp\u003eUnivarite analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHRs\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\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHRs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHRs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eHRs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years old)\u003c/p\u003e \u003cp\u003e\u0026le; 60 vs\u0026thinsp;\u0026gt;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.741\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.405\u0026ndash;1.353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.327\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.915\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.374\u0026ndash;2.239\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.843\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (mm)\u003c/p\u003e \u003cp\u003e\u0026le; 50.0 vs\u0026thinsp;\u0026gt;\u0026thinsp;50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.582\u0026ndash;1.960\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.812\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.743\u0026ndash;4.472\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.191\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin infiltration\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.821\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.453\u0026ndash;1.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.528\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.770\u0026ndash;7.370\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node metastasis\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.890\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.380\u0026ndash;2.601\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.811\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.673\u0026ndash;59.065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe number of distant metastatic organs\u003c/p\u003e \u003cp\u003eSingle vs Multiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.708\u0026ndash;2.315\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.411\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.940\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.795\u0026ndash;5.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone metastases\u003c/p\u003e \u003cp\u003eNo vs Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.550\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.855\u0026ndash;2.883\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.149\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.896\u0026ndash;6.532\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.989\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.765\u0026ndash;5.814\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung metastases\u003c/p\u003e \u003cp\u003eNo vs Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.245\u0026ndash;0.831\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.433\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.225\u0026ndash;0.838\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.211\u0026ndash;1.339\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver metastases\u003c/p\u003e \u003cp\u003eNo vs Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.277\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.299\u0026ndash;7.246\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.550\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.005\u0026ndash;5.684\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.007\u0026ndash;10.451\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.644\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.664\u0026ndash;9.051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstrogen receptor\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.488\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.146\u0026ndash;3.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.376\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.700\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.141\u0026ndash;12.697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.744\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgesterone receptor\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.179\u0026ndash;0.666\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.439\u0026ndash;13.159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.222\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.199\u0026ndash;1.187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone receptor\u003c/p\u003e \u003cp\u003eEither ER\u0026thinsp;+\u0026thinsp;or PgR\u0026thinsp;+\u0026thinsp;vs Both ER and PgR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.319\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.164\u0026ndash;0.612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.050\u0026ndash;1.273\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.464\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.186\u0026ndash;1.130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.143\u0026ndash;1.232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003c/p\u003e \u003cp\u003eNegative vs Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.445\u0026ndash;9.614\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.227\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi67\u003c/p\u003e \u003cp\u003eLow vs High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.578\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.836\u0026ndash;2.867\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.155\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.992\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.320\u0026ndash;2.597\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.988\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine therapy\u003c/p\u003e \u003cp\u003eLH-RH agonist\u0026thinsp;+\u0026thinsp;TAM vs Other\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.560\u0026ndash;2.279\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.810\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.525\u0026ndash;5.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.501\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response rate\u003c/p\u003e \u003cp\u003eNon-Responders vs Responders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.325\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.173\u0026ndash;0.624\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.176\u0026ndash;0.799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.437\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.174\u0026ndash;1.107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.217\u0026ndash;1.652\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.305\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCriteria for disease progression\u003c/p\u003e \u003cp\u003eIncreased of existing tumor vs\u003c/p\u003e \u003cp\u003eAppearance of new metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.645\u0026ndash;2.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.512\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.878\u0026ndash;6.138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e3.762\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.242\u0026ndash;11.394\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoker\u003c/p\u003e \u003cp\u003eNo vs Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.476\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.780\u0026ndash;2.694\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.224\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.555\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.608\u0026ndash;3.767\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.343\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"16\"\u003ePFS: progression-free survival. OS: overall survival, HRBC: hormone receptor-positive breast cancer. HRs: hazard ratios. CI: confidence intervals. ER: estrogen receptor. PgR: Progesterone receptor. HER2: human epidermal growth factor receptor 2. LH-RH: luteinizing hormone-releasing hormone. TAM: tamoxifen.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding the criteria for disease progression, the log-rank test also showed that the prognosis of patients with new metastatic lesions was not significantly different for PFS (p\u0026thinsp;=\u0026thinsp;0.506, log-rank) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), but OS tended to be worse (p\u0026thinsp;=\u0026thinsp;0.064, log-rank) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSmoking, which has been reported to be a poor prognostic factor in breast cancer treatment [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], was also associated with poor PFS in patients with first-line endocrine treatment in this study. This is because tobacco components have been reported to cause a more malignant biology [\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Among these studies, this study is positioned as a rare report that smoking affects the progression of breast cancer during endocrine treatment. In a report examining the correlation between smoking and clinicopathological features in estrogen receptor-positive and HER2-negative early-stage breast cancers, most clinicopathological features were not found to correlate with smoking [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, lymphovascular invasion was significantly more frequent in smokers than in non-smokers[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. There are few reports examining the correlation between smoking and clinicopathological factors except for that report, but some studies have been conducted in vivo and in vitro. For example, it has been reported that nicotine, which is one of the main components of cigarette smoke, enhances both the cell proliferation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and the metastatic abilities of tumors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. There are also some reports that tobacco induces inflammation in the tumor microenvironment, which results in a metastatic environment[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These biological changes may have led to the results of this study.\u003c/p\u003e \u003cp\u003eThe appearance of new distant metastases during the course of treatment is also a poor prognostic factor [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In this study, smokers had a poor prognosis as smoking affected the progression of breast cancer. However, smoking affected PFS but not OS. In contrast, the criteria for disease progression in other studies were not based on the PFS but on a poor prognosis based on the OS, causing disparities in the results. The cause of this was not clear in this study. Chemotherapy may have been performed after primary endocrine therapy. It has been suggested that pharmacokinetic interactions with smoke components may affect the efficacy and toxicity of chemotherapy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. It has been reported that smoking affects the tumor immune microenvironment and temporarily affects the therapeutic effect of chemotherapy, which may be one of the causes [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne of the major limitations of this study was the small number of cases. Furthermore, the evaluation of smoking was not accurate because it was based on the results of an interview. Passive smoking is also a risk factor for breast cancer carcinogenesis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]; therefore, passive smoking may also affect prognosis and alter the biology. However, the fact that smoking is not only involved in breast cancer carcinogenesis but also shows a difference in the progression of breast cancer suggests that it may also affect the biology. Although not an experiment with breast cancer cells, there are some reports that tobacco extract reduces E-cadherin in cancer cells [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. It has been reported that the attenuation of E-cadherin expression is involved in breast cancer metastasis [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], which may be one of the causes. In the future, it will be necessary to investigate protein expression by immunohistochemical staining and changes in gene expression by reverse transcriptase-polymerase chain reaction using clinical specimens.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn stage IV HRBC, smoking increases the metastatic potential of breast cancer, suggesting that changes in its biology may lead to poor prognosis. Stage IV HRBC in heavy smokers should be treated with caution because of the emergence of distant metastases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eANA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eanastrozole\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ecCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eclinical complete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ecPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eclinical progressive disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ecPR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eclinical partial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ecSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eclinical stable disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eER\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eestrogen receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHER2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehuman epidermal growth factor receptor 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehazard ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehormone receptor-positive breast cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLH-RH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eluteinizing hormone-releasing hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eobjective response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePgR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogesterone receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTAM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etamoxifen.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA written informed consent to participate in the study was obtained from each subject in accordance with the declaration of Helsinki principles.\u0026nbsp;Each patient or the patient\u0026rsquo;s family was fully\u0026nbsp;informed of the investigational nature of this study and provided their written, informed consent. The study protocol was approved by the Ethics Committee of Osaka City University (approve number #926).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported in part by Grants-in-Aid for Scientific\u0026nbsp;Research (KAKENHI\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eNos. 17K10559,\u0026nbsp;19K18067 and 20K08938) from the Ministry of\u0026nbsp;Education, Science, Sports, Culture and Technology of Japan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKT participated in the design of the study and drafted the manuscript. SK participated in the design of the study and\u0026nbsp;manuscript editing. AY, NI, WG, YA, YT, TM and KO helped with study data collection and manuscript preparation. MS\u0026nbsp;and MO conceived the study,\u0026nbsp;and participated in its design and coordination\u0026nbsp;and\u0026nbsp;helped to draft the manuscript. All\u0026nbsp;authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Tomomi Okawa (Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine)\u0026nbsp;for helpful advice regarding data management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eDepartment of\u0026nbsp;Gastroenterological\u0026nbsp;Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHortobagyi GN: \u003cb\u003eTreatment of breast cancer\u003c/b\u003e. N Engl J Med 1998, \u003cb\u003e339\u003c/b\u003e:974\u0026ndash;984.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDossus L, Boutron-Ruault MC, Kaaks R, Gram IT, Vilier A, Fervers B, Manjer J, Tjonneland A, Olsen A, Overvad K, et al: \u003cb\u003eActive and passive cigarette smoking and breast cancer risk: results from the EPIC cohort\u003c/b\u003e. Int J Cancer 2014, \u003cb\u003e134\u003c/b\u003e:1871\u0026ndash;1888.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePierce JP, Patterson RE, Senger CM, Flatt SW, Caan BJ, Natarajan L, Nechuta SJ, Poole EM, Shu XO, Chen WY: \u003cb\u003eLifetime cigarette smoking and breast cancer prognosis in the After Breast Cancer Pooling Project\u003c/b\u003e. 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Biomark Res 2017, \u003cb\u003e5\u003c/b\u003e:19.\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":"breast cancer, smoking, hormone receptor, endocrine therapy, cigarette","lastPublishedDoi":"10.21203/rs.3.rs-1365423/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1365423/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBackground\u003c/em\u003e:\u003c/strong\u003e Smoking worsens breast cancer prognosis. It has been reported that tobacco components directly reach mammary gland tissue, causing smoking-related DNA damage and biological effects. We hypothesized that smoking may have a characteristic course other than the therapeutic effect in patients with stage IV hormone receptor-positive breast cancer (HRBC) who received endocrine therapy as the first-line treatment.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods\u003c/em\u003e:\u003c/strong\u003e Fifty-six patients diagnosed with stage IV HRBC were treated with endocrine therapy as the first-line treatment. Before treatment, the period and amount of smoking were confirmed through patient interviews, and each pack-year was recorded.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResults\u003c/em\u003e:\u003c/strong\u003e It was significantly more frequent for smokers to be evaluated for disease progression due to the appearance of new metastases during endocrine therapy as first-line treatment (p=0.034). Furthermore, as the pack-year increased, new metastases tended to appear (pack-year ≤15; hazard ratio [HR] 1.929, p=0.507; pack-year 15–30, HR 3.857, p=0.223; pack-year \u0026gt;30, HR: 7.714, p=0.028).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConclusions\u003c/em\u003e: \u003c/strong\u003eIn stage IV HRBC, smoking increases the metastatic potential of breast cancer, suggesting that changes in its biology may lead to poor prognosis.\u003c/p\u003e","manuscriptTitle":"Effect of Smoking on Endocrine Therapy for Stage IV Hormone Receptor Positive Breast Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-03-10 15:52:30","doi":"10.21203/rs.3.rs-1365423/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":"e2685ed5-691e-403b-bf7e-7e446ebef8a1","owner":[],"postedDate":"March 10th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-03-29T10:29:21+00:00","versionOfRecord":[],"versionCreatedAt":"2022-03-10 15:52:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1365423","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1365423","identity":"rs-1365423","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}