Search

(Background)Eribulin, a non-taxane inhibitor of microtubule dynamics, is a unique chemotherapy agent for locally advanced or metastatic breast cancer (MBC). The treatment has been demonstrated to extend overall survival (OS) without extending progression-free survival (PFS). This effect seems to result from the suppression of epithelial-mesenchymal transition (EMT) and improvement of the hypoxic microenvironment by vascular normalization induced by eribulin, directly or indirectly. In a previous study, we identified that high absolute lymphocyte count (ALC) at the baseline was significantly associated with longer OS in the eribulin group, but not in the treatment of physician’s choice (TPC) group, in the phase III EMBRACE trial (Miyoshi et al., Breast Cancer, 2020). These results strongly suggest an association between eribulin efficacy and immune response. Therefore, we focused on serum levels of immune and inflammatory cytokines,which are expected to have greater utility as a predictive factor for eribulin than ALC. Interleukin (IL) 6, an inflammatory cytokine associated with cancerprogression, and soluble interleukin-2 receptor (sIL-2R), a receptor of IL-2 released from various immune cells including T cells, B cells, and natural killer cells, were selected for the investigation. (Patients and methods)A total of 44 patients treated with eribulin for MBC were recruited for the study. We examined the predictive values of IL-6 and sIL-2R in addition to the neutrophil-to-lymphocyte ratio (NLR) and ALC at baseline. The cutoff values of NLR and ALC were set at 3.0 and 1500/μL, respectively. We used the normal ranges of IL-6 (4.0 pg/mL) and sIL-2R (474 U/mL) as cutoff values. (Results)The OS of patients with low NLR (n=28) and high ALC (n=17) were significantly longer than that of patients with high NLR (n=16, p=0.0287) and low ALC (n=27, p=0.0234). There were no significant associations between PFS and NLR or ALC (p=0.0852 and p=0.2231, respectively). Patients with normal IL-6 levels (n=17) had significantly longer PFS (p=0.0023) and OS (p=0.0013) than those with elevated IL-6 levels (n=27). Regarding sIL-2R, patients with normal sIL-2R levels (n=18) had longer OS (p=0.0483) than those with elevated sIL-2R levels (n=26), but their PFS was similar (p=0.2435). Multivariate analysis showed that IL-6 levels were only significantly associated with OS (hazard ratio, 0.093; 95% confidence interval, 0.012-0.720; p=0.0106). There was no significant association between IL-6 levels and NLR or ALC. (Conclusion and discussion)Patients treated with eribulin demonstrated a significantly longer OS if their baseline IL-6 levels were within the normal range. This predictive efficacy for eribulin was more accurate than that of NLR or ALC. As there was no significant association between IL-6 levels and NLR or ALC, IL-6 appears to predict whether the tumor microenvironment is favorable or unfavorable for eribulin treatment, mediated through different mechanisms. Therefore, IL-6 levels may be useful for selecting patients who will benefit from the administration of eribulin in terms of improved OS. Citation Format: Ayako Bun, Natsuko Inoue, Yoshimasa Miyagawa, Reiko Fukui, Yukie Fujimoto, Tomoko Higuchi, Atsushi Sata, Hiromi Ozawa, Michiko Imamura, Yasuo Miyoshi. Low levels of interleukin-6 at baseline were significantly associated with improved overall survival of patients treated with eribulin for locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-20.

Background Vascular endothelial growth factor (VEGF) is a key player in angiogenesis, and bevacizumab, a humanized monoclonal antibody against VEGF-A, is already utilized in daily clinical practice coupled with chemotherapy for locally advanced and metastatic breast cancers (ABC). Although the impact of bevacizumab plus paclitaxel therapy on PFS was prominent, no OS benefit has been demonstrated so far. Identification of a robust biomarker for bevacizumab therapy in terms of benefit on OS is a critical issue. Since VEGF modulates various functions of cancer immunity, direct inhibition of VEGF, in addition to vascular normalization by bevacizumab may lead to improvement of immune microenvironment, resulting in favorable prognosis in patients. On the basis of this aspect, predictive efficacy of peripheral immune related parameters were investigated in patients treated with bevacizumab plus paclitaxel. Method A total of 182 patients with locally advanced and metastatic breast cancers treated with bevacizumab plus paclitaxel were retrospectively recruited from three institutes. We measured neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and c-reactive protein (CRP) in the peripheral blood taken at baseline (the same day just before start of 1st treatment). Bevacizumab 10 mg/kg on days 1 and 15 and paclitaxel 80 or 90 mg/m2 on day 1, 8, and 15 of each 28-day cycle were administered intravenously. The cut-off values of NLR, ALC, and CRP were set at 3, 1500/μL, and 1.0mg/dL, respectively and baseline values of these factors were measured. Results We divided the patients into NLR-high (n=101) and -low (n=81); CRP-high (n=62) and -low (n=89). The progression-free survival (PFS) of patients with NLR-low was significantly longer than that of patients with NLR-high (median, 12.6 vs. 7.2 months; hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.31-0.70; p=0.0002). In addition, OS of patients with NLR-low was significantly better than those with -high (22.2 vs. 13.5 months; HR, 0.55; 95% CI, 0.38-0.80; p=0.0017). Similarly, improved PFS and OS were recognized in patients with CRP-low as compared with -high (HR, 0.42; 95% CI, 0.27-0.66; p Citation Format: Hiromi Ozawa, Yoshimasa Miyagawa, Ayako Yanai, Takehiro Yanagawa, Jyunichi Inatome, Chiyomi Egawa, Arisa Nishimukai, Kaori Takamoto, Takashi Morimoto, Atsushi Sata, Reiko Fukui, Ayako Bun, Tomoko Higuchi, Yukie Fujimoto, Michiko Imamura, Yasuo Miyoshi. Baseline neutrophil-to-lymphocyte ratio and C-reactive protein predict efficacy of bevacizumab plus paclitaxel therapy for locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-49.

Background Endocrine therapy is an essential treatment choice for patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative locally advanced and metastatic breast cancers. Although patients with non-visceral metastasis or with favorable efficacy induced by prior endocrine therapy, are reported to be associated with a longer duration of endocrine therapy, predictive markers have yet to be established. In general, breast cancers with low proliferative activity and small tumor burden seem to obtain favorable efficacy induced by endocrine therapy. Metabolic tumor volume (MTV) on fluorodeoxyglucose-positron emission tomography (FDG-PET) examination measures uptake activity of glucose in tumor cells, which represents tumor aggressiveness, and tumor volume. Thus, using MTV as a metabolic parameter for both proliferative activity and tumor burden, we evaluated the predictive usefulness of MTV for treatment efficacy of endocrine therapy.MethodA total of 83 patients treated with endocrine therapy for locally advanced and metastatic breast cancers, treated with an aromatase inhibitor (AI; n=39) or fulvestrant (Ful; n=44), examined by FDG-PET before start of treatment, were constitutively recruited in this retrospective study. The treatment lines were as follows; 1st, n=46; 2nd, n=22; 3rdor more, n=15. The maximum value of the standard uptake value (SUV, regional radioactivity concentration (Bq/mL)/injected dose (Bq)/patient weight (g)) in the volume of interest (VOI) was defined as the SUVmax. Total volume of voxels of ≥40% of the SUVmax in the VOI was defined as the MTV. The cut-off value of MTV was defined at 45 and the relationships between MTV and progression-free survival (PFS) was calculated.ResultsPFS of patients treated with Ful (median, 19.0 months) was marginally favorable than those with AI (median, 9.8 months; p=0.084). In all participants, PFS of patients with low levels of MTV (n=29; median, 23.6 months) was significantly longer than those with high levels (n=54; median, 10.0 months; p=0.0124). The association between low levels of MTV and longer PFS was significantly (p=0.0369) and marginally (p=0.0715) recognized in Ful and AI, respectively. Similarly, association between MTV and PFS seems to be consistent in subgroups in visceral or non-visceral metastasis, de novo or recurrence, and treatment lines.Discussion and conclusionIn the present study, we demonstrated that low levels of MTV at baseline are significantly associated with longer PFS for patients treated with AI or Ful. MTV seems to be a predictor for the efficacy of endocrine therapy by evaluating both tumor aggressiveness and tumor volume. This data may be useful in selecting patients who could benefit from endocrine therapy with non-invasive method. Citation Format: Reiko Fukui, Tomoko Higuchi, Yukie Fujimoto, Atsushi Sata, Ayako Bun, Hiromi Ozawa, Hiromi Ozawa, Yoshimasa Miyagawa, Michiko Imamura, Kazuhiro Kitajima, Yasuo Miyoshi. Low levels of metabolic tumor volume at baseline significantly associated with longer progression-free survival in patients with locally advanced or metastatic breast cancer treated with endocrine therapies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-30.

The effect of bevacizumab plus paclitaxel therapy on progression-free survival (PFS) is prominent; however, no overall survival (OS) benefit has been demonstrated. Our aim was to study the predictive efficacy of peripheral immune-related parameters, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and c-reactive protein (CRP) in locally advanced and metastatic breast cancers. A total of 179 patients treated with bevacizumab plus paclitaxel were recruited from three institutes in the test cohort. The cut-off values of NLR, ALC, and CRP were set at 3, 1500/μL, and 1.0 mg/dL, respectively, and baseline values of these factors were measured. The PFS of patients with NLR-low was significantly longer than that of patients with -high (median, 12.6 vs. 7.2 months; hazard ratio (HR), 0.48, 95% confidence interval (95% CI), 0.31–0.73; p = 0.0004). OS of patients with NLR-low was significantly better than those with-high (22.2 vs. 13.5 months; HR, 0.57, 95% CI, 0.39–0.83; p = 0.0032). Similarly, improved PFS and OS were recognized in patients with CRP-low as compared with patients with -high (HR, 0.44, 95% CI, 0.28–0.68; p = 0.0001 and HR, 0.39, 95% CI, 0.26–0.61, p < 0.0001, respectively). In the validation cohort from two institutes (n = 57), similar significant improvements in PFS and OS were confirmed for patients with NLR-low (p = 0.0344 and p = 0.0233, respectively) and CRP-low groups (p < 0.0001 and p = 0.0001, respectively). Low levels of NLR and CRP at baseline were significantly associated with improved prognosis in patients treated with bevacizumab plus paclitaxel.

Background/aim Factors influencing fulvestrant efficacy may be useful in selecting the optimal treatment regimen for postmenopausal Japanese women with metastatic/recurrent HR-positive, HER2-negative breast cancer. Patients and methods We retrospectively evaluated progression-free and overall survival (PFS and OS) in 100 fulvestrant-treated patients according to metastatic site. Results Median PFS was significantly better in patients with non-visceral (bone and regional metastases; 22.8 months) vs. visceral metastasis (lung, liver, and other organs; 8.2 months; p=0.024), although median OS did not differ (p=0.922). Median PFS in patients with lung metastasis (20.8 months) and non-visceral metastasis (22.8 months) were comparable; patients with liver metastasis (6.1 months) and other organ metastases (3.7 months) had worse prognoses. Conclusion Patients with non-visceral metastases had a better prognosis than those with visceral metastases. Fulvestrant induced a longer PFS in patients with non-visceral metastasis, and also in those with lung metastasis without liver or other organ involvement.

Purpose The prognosis of human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancers (MBCs) has dramatically improved due to the introduction of trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1). The efficacy of T-DM1 is prolonged for some patients; however, the predictive factors remain unknown. There is a report that T-DM1 induced antitumor immunity in patients treated with neoadjuvant therapy, with tumor infiltrating lymphocytes (TILs) increasing after the administration of T-DM1. Based on these observations, the benefits of T-DM1 for prognosis may be mediated by an immune reaction against breast cancers, at least in part. As an indicator of cancer immunity, in addition to TILs, the neutrophil-to-lymphocyte ratio (NLR) has been established in early breast cancers. In the present study, we investigated the usefulness of the NLR for treatment efficacy of T-DM1 in HER2-positive MBCs. Methods Fifty-three advanced or metastatic breast cancers treated with T-DM1 were retrospectively recruited from three institutes. The NLR in the peripheral blood was measured at baseline (just before the start of T-DM1) and after one cycle (just before the start of cycle 2). The cutoff value of the NLR was set at 2.56 (median value) and progression-free survival (PFS) and overall survival (OS) according to NLR levels were evaluated. Results The PFS of patients with NLR-low at baseline (NLR Citation Format: Imamura M, Morimoto T, Egawa C, Miyagawa Y, Miyoshi Y. Significance of baseline neutrophil-to-lymphocyte ratio for progression-free survival of patients with HER2-positive locally advanced and metastatic breast cancer treated with trastuzumab emtansine [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-19.

Background/aim We investigated the efficacy of neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and C-reactive protein (CRP) in predicting overall survival of metastatic breast cancer patients treated with eribulin. Patients and methods Overall, 74 patients treated with eribulin were enrolled and their baseline levels of NLR, ALC, and CRP retrieved. Cutoff values of NLR, ALC, and CRP were set at 3.0, 1500/μl, and 0.3 mg/dl, respectively. Overall survival (OS) was compared according to marker levels. Results The OS of NLR-low, ALC-high, and CRP-low groups at baseline was significantly longer than that of NLR-high, ALC-low, and CRP-high groups (p=0.0027, p=0.0013, and p=0.0164, respectively). The combination of ALC and CRP was significantly associated with OS by multivariate analysis (p=0.048). Conclusion Baseline levels of NLR, ALC, and CRP were significantly associated with OS in patients treated with eribulin. The combination of ALC and CRP improved the predictive efficacy compared to individual markers.

BACKGROUND/AIM This study aimed to improve the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs). PATIENTS AND METHODS In this retrospective study, NLR and TIL data from 677 operated breast cancer patients were analysed. The cut-off value of NLR was set at 2.72, and TIL levels were classified as low (

Although eribulin and nab-paclitaxel are chemotherapy agents widely used for locally advanced or metastatic breast cancer (MBC), their predictive factors remain unknown. Because the absolute neutrophil-to-lymphocyte ratio (NLR) is a significant prognostic factor for early-stage breast cancer, we investigated its usefulness in terms of the eribulin or nab-paclitaxel treatment efficacy for MBC.A total of 85 patients with MBC treated with eribulin (n = 59) or nab-paclitaxel (n = 26) were recruited. NLR values were collected at baseline, after 1 cycle, after 2 cycles, and at the end of treatment. The NLR cutoff value was set at 3.The progression-free survival (PFS) of patients with an NLR 3 at baseline (median, 242 days; n = 24) was significantly better than that of patients with an NLR of ≥ 3 (median, 98 days; n = 35; hazard ratio, 0.37, 95% confidence interval, 0.18-0.71; P = .0032). Similarly, the overall survival was marginally significantly better in patients with an NLR 3 who were treated with eribulin (P = .058). However, the NLR was not significantly associated with PFS or overall survival for patients treated with nab-paclitaxel. No significant association was found between the NLR during treatment and PFS in the eribulin group. The significance of the NLR for the efficacy of eribulin was consistent, irrespective of estrogen receptor status, previous anthracycline or endocrine use, and the number of previous chemotherapy regimens.A low NLR at baseline was significantly associated with improved PFS in patients treated with eribulin but not in those treated with nab-paclitaxel. Therefore, the baseline NLR might be clinically useful for selecting patients who would benefit from eribulin.

Background and objectives To identify surrogate markers for prognosis of breast cancer patients with non-pathological complete response (non-pCR) to neoadjuvant chemotherapy (NAC), our investigation focused on the serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA15-3) as well as clinicopathological factors both before and after NAC. Methods A total of 185 breast cancer patients treated with NAC were recruited. Serum carcinoembryonic antigen and CA15-3 were measured at baseline and at completion of NAC. Results Among the non-pCR cancers (n = 142), the disease-free survival (DFS) of patients with CA15-3-low at baseline (3-year DFS: 0.908, n = 73) was significantly better than of those with CA15-3-high (3-year DFS: 0.681, n = 69, P = .0134). Multivariable analysis demonstrated that baseline CA15-3 levels (hazard ratio: 3.31, 95% confidence interval: 1.28-10.23; P = .0122) and residual invasive size (hazard ratio: 4.47, 1.26-28.39; P = .0171) were significant independent factors for DFS. The combination of these factors proved to be an accurate predictor for DFS regardless of breast cancer subtypes. Conclusions The combination of residual invasive size and serum CA15-3 levels at baseline seems to be a significant and independent surrogate marker of poor outcome for patients with non-pCR. These findings suggest that these markers may be useful for identifying patients with inferior prognosis and candidates for additional adjuvant treatments.

Background: Tumor-infiltrating lymphocytes might be a one of predictive outcome of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) patients (pts) who treated with trastuzumab and pertuzumab (TP) plus docetaxel. Although peripheral blood-based parameter (PBBP) is reported as a prognostic indicator of patients with early breast cancers, utility of PBBP has not been studied in HER2-positive ABC. Objective:The aim of our study was to determine whether PBBP is significant for predictive efficacy in HER2-positive ABC treated with TP combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). Methods: The 51 patients' data from two single arm phase II trials was included in this retrospective-prospective study; ERI + TP (n=30) or Nab-PTX + TP (n=21) registered with UMIN000012375 or UMIN000006838, respectively. We assessed the PBBP in prospectively collected data and investigated their association with progression-free survival (PFS). In consideration of PBBP, we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values of ALC, NLR, and PLR were set at 1000 cells/μL, 2, and 250, respectively. Results:Median age at baseline was 58 years (range: 31-77). Median number of previous chemotherapy was 3 (range: 1-10). Pts had multiple metastases, 53% with LNs, 35% with bone, 25% with lung, 20% with liver, and 6% with brain. The objective response rate (CR+PR) and clinical benefit rate (CR+PR+ more than 6 month SD) were 37% (n=19) and 59% (n=30), respectively. The median PFS of all pts was 301 days (range: 21-1281). The PFS of pts with ALC-High was significantly better than those of ALC-low (hazard ratio (HR): 2.74, 95% confidence interval (CI): 1.28 to 5.86; p= .0097). Furthermore, improved PFS was obtained in pts with ALC greater than 1500 cells/μL compared with less than 1000 cells/uL (HR: 4.05, 95% CI: 1.60 to 11.6; p= .0029). Significant associations seem to exist irrespective of number of previous chemotherapy. Since we combined different studies for evaluating PBBP, ERI and Nab-PTX were calculated separately. Marginally significant associations between ALC and PFS were obtained both in ERI (HR: 2.18, 95% CI: 0.87 to 5.60; p=.0973) and Nab-PTX (HR: 3.26, 95% CI: 0.80 to 12.4; p=.0939). The PFS of NLR-low pts was significantly better than those of NLR-high (HR: 2.29, 95% CI: 1.01 to 5.90; p= .0477), but this statistical difference was inferior to those of ALC. There was no significant association between PLR and PFS. Conclusions: Pre-treatment ALC-High was significantly correlated with favorable PFS of pts treated with TP irrespective of combination chemotherapy in HER2-positve ABC. Prolonged PFS of TP combination therapy might be obtained mediating through host systemic onco-immunity. These data obtained here suggest that a usefulness of ALC for selecting pts who might have clinical benefit from TP combination therapy for heavily treated HER2-positve ABC. Citation Format: Araki K, Ito Y, Fukada I, Kobayashi K, Ohno S, Miyagawa Y, Imamura M, Kira A, Takatsuka Y, Egawa C, Suwa H, Miyoshi Y. Predictive impact of absolute lymphocyte counts for progression-free survival in HER2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-31.

Background: It has been well demonstrated that patients who achieved pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) had a favorable prognosis compared with patients who did not (non-pCR). Even though pCR was not attained, reduction in tumor volume after chemotherapy may be associated with improved prognosis for a certain number of patients. However, the association between residual tumor volume and prognosis is not necessarily consistent. In order to identify substitute markers for breast cancer patients with non-pCR after NAC, we investigated the impact of serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA15-3) at baseline as well as post-NAC. Patients and Methods: Ninety-six breast cancer patients treated with NAC and operated on at the Hyogo College of Medicine were recruited for this study. Serum CEA and CA15-3 were measured prior to chemotherapy as well as at completion of pre-operative treatment. The optimal cutoff points for CEA (1.55ng/m, normal range: Results: pCR and non-pCR was attained by 21 and 75 patients, respectively. For the non-pCR patients, serum CEA levels at baseline were classified into high (n=35) and low (n=38) and serum CA15-3 levels at baseline into high (n=31) and low (n=43). RFS of non-pCR patients with high serum CA15-3 levels was significantly worse than of those with low levels (3-year RFS: 0.47 vs 0.93; p=0.0009). RFS for patients with high and low serum levels of CA15-3 after NAC was also significantly different (p=0.037). As for CEA, no significant association with RFS was observed either at baseline or post-NAC. Univariate analysis demonstrated that tumor size and baseline CA15-3 were significant prognostic factors for RFS. Multivariate analysis showed that both tumor size (hazard ratio (HR): 3.88, 95% confidence interval (CI): 1.21-12.35, p=0.023) and baseline CA15-3 (HR: 13.51, 95% CI: 1.74-105.08, p=0.013) were significant and independent risk factors for relapse. As for lymph node metastasis, tumor grade, residual tumor size and pre- and post-NAC Ki67 expression levels of patients with non-pCR showed no significant association with RFS. Conclusion and discussion: High levels of serum CA15-3 at baseline constituted a significantly worse prognosis for breast cancer patients with non-pCR. Tumor size at baseline but not residual size and baseline CA15-3 seems to suitable as a substitute for prediction of outcome for patients with non-pCR. Our findings suggest that these markers may be useful for identifying patients with poor prognosis who may be candidates for additional adjuvant treatment. Citation Format: Fujimoto Y, Imamura M, Higuchi T, Nishimukai A, Yanai A, Miyagawa Y, Murase K, Takatsuka Y, Miyoshi Y. Baseline serum CA15-3 levels are associated with prognosis for breast cancer patients with non-complete pathological response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-27.

Adjuvant treatments for operable breast cancers are determined according to subtypes defined based on estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status. The ER+/HER2− subtype can be divided into luminal A and luminal B usually by Ki67 expression levels. Although tumor size, lymph node metastasis and tumor grade have been widely accepted in daily clinical practice, the identification of further prognostic indicators especially in the ER+/HER2− subtype is warranted. A total of 387 operated breast cancers for which maximum standardized uptake value (SUVmax) on the 18 F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) were available at baseline were retrospectively analyzed. The optimal cutoff value of SUVmax for relapse-free survival (RFS) was determined to be 3.585 by means of the receiver operating characteristics curve with an area under the curve of 0.6795 (95% CI: 0.5972 to 0.7618, p = 0.0006, sensitivity: 78.8%, specificity: 57.1%). The RFS of patients with SUVmax-high (n = 178) was significantly (p = 0.0003) worse compared with those with SUVmax-low (n = 209). This significant association was prominently recognized in the ER+/HER2− subtype. By multivariable analysis, SUVmax (hazard ratio: 3.83, 95% confidence interval: 1.28–11.51, p = 0.017), tumor size (4.22, 1.39–12.82, p = 0.011) and lymph node metastasis (4.44, 1.81–10.87, p = 0.0012) were significant and independent prognostic factors for RFS. The ER+/HER2− subtype demonstrated consistently worse RFS in the SUVmax-high patients both in the luminal A (p = 0.037) and luminal B (p = 0.047) subtypes. Combination of Ki67 and SUVmax appears to be useful for selecting patients who have inferior prognosis and need further adjuvant treatment of the ER+/HER2− subtype.

The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been established in breast cancers with estrogen receptor (ER)-negative and human epithelial growth factor receptor 2 (HER2)-negative or HER2-positive subtypes; however, its utility concerning the ER + /HER2 - subtype remains unclear.We evaluated the prognostic value of TILs by analyzing 717 invasive breast cancer operation cases. TILs were classified into three groups based on the proportion of area within the tumor: low ( 10%), intermediate (10-50%), and high ( 50%). Disease-free survival (DFS) and overall survival (OS) were calculated according to TIL levels.Although there was no significant association between TIL levels and DFS or OS in all patients, high TILs were significantly associated with favorable DFS in Ki67-high (n = 238, p = 0.035) but not in Ki67-low (n = 470, p = 0.46) breast cancers. Multivariable analysis showed that high TILs were a significant and independent factor for DFS (HR 0.34; 95% CI 0.10-0.87; p = 0.023) among the Ki67-high group. In the ER + /HER2 - subtype, high-TILs showed favorable DFS in the Ki67-high group, although this was not statistically significant (p = 0.48); in contrast, unfavorable DFS was observed in the Ki67-low group (p = 0.027).In Ki67-high breast cancers, high TILs were associated with favorable DFS, irrespective of subtype, but increasing TIL levels correlated with worse DFS in the Ki67-low group with the ER + /HER2 - subtype. These results highlight variation in TIL prognostic significance between Ki67-high and -low breast cancers, particularly for the ER + /HER2 - subtype.

Although the neutrophil-to-lymphocyte ratio (NLR) is a valuable prognostic factor for early breast cancer, the patient subgroups that may benefit the most from NLR analysis remain unknown. The present study analyzed the prognostic significance of NLR according to absolute lymphocyte counts (ALCs). A total of 889 patients with operated early breast cancers were retrospectively recruited. Existing NLR and ALC baseline data from the time-period prior to operation or preoperative chemotherapy were collected. The cut-off value for NLR was set at 2.72 according to the receiver operating characteristic curve. Recurrence-free survival (RFS) of NLR-low patients at baseline (n=582) was significantly better than that of NLR-high patients (n=307, P=0.036). Improved patient prognoses were observed in the NLR-low, ALC-high (>1,688/µl; 5-year RFS, 0.88 vs. 0.57; P

Background: Bone-modifying agents have demonstrated their efficacy for treatment by suppressing osteoclast function. The activity of bone-modifying agents can be monitored by means of bone resorption markers such as c-terminal crosslinking telopeptide of type I collagen (1CTP) and N-telopeptide of type I collagen (NTX) as well as bone forming marker bone-specific alkaline phosphatase (BAP). In contrast to these markers which indirectly indicate bone turnover, tartrate-resistant acid phosphatase-5b (Tracp-5b) has been established as a direct marker showing osteoclast number and activity. The aim of this study was to identify the relative significance of these bone turnover markers as indicators of treatment efficacy induced by bone-modifying agents for breast cancer patients with bone metastases. Patients and Methods: For this study, 52 breast cancer patients with bone metastases treated with bone-modifying agents were recruited. Zoledronic acid and denosumab were administered as bone-modifying agents to 36 and 22 patients, respectively (for 6 patients, denosumab was used after zoledronic acid). Serum Tracp-5b, 1CTP, NTX and BAP were measured with, respectively, the EIA (enzyme immunoassay), RIA (two-antibody radioimmunoassay), ELISA (enzyme-linked immunosorbent assay) and CLEIA (chemiluminescent enzyme immunoassay) method. Blood samples were obtained pretreatment and 1, 3 and 6 months after treatment. Changes in these bone turnover markers were statistically analyzed with Friedman's test, and correlation between serum markers and clinicopathological factors was calculated with Mann-Whitney's test. Results: Serum tracp-5b decreased significantly after treatment (p Conclusion and discussion: Although baseline values of the bone turnover markers Tracp-5b, NTX and BAP decreased significantly after treatment with bone-modifying agents, the pattern of reduction for these three markers varied. Tracp-5b appears to reflect efficacy of bone-modifying agents most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings may prove usefulness of Tracp-5b when considering the efficacy of various bone-modifying agents in clinical practice. Citation Format: Higuchi T, Nishimukai A, Yanai A, Miyagawa Y, Murase K, Imamura M, Ozawa H, Takatsuka Y, Miyoshi Y. Differences in patterns of change of bone turnover markers during treatment with bone-modifying agents of breast cancer patients with bone metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-16-01.

Background: It has been demonstrated that adjuvant treatment using bisphosphonate may reduce recurrence among breast cancer patients. However, these improved prognoses of patients are reportedly limited to breast cancers of estrogen receptor (ER)-positive and postmenopausal women. Although the mechanisms of the effects of bisphosphonate remain unknown, this finding seems to represent support for the hypothesis that suppression of bone resorption by bisphosphonate results in favorable prognoses at least for patients in this subset. In order to determine the prognostic significance of bone resorption in breast cancer patients, we investigated these markers c-terminal crosslinking telopeptide of type I collagen (1CTP) and N-telopeptide of type I collagen (NTX). Patients and Methods: 469 breast cancer patients were recruited who were operated on Hyogo College of Medicine and histologically confirmed to have invasive carcinoma. Serum 1CTP and NTX were measured preoperatively with the two-antibody radioimmunoassay and enzyme-linked immunosorbent assay methods, respectively, and blood samples were obtained before treatment from patients who were treated with neoadjuvant chemotherapy or endocrine therapy. The area under receiver operating characteristic curves were applied and optimal cutoff values were set at 3.6ng/ml for 1CTP, and 10.55nmolBCE/L premenopausal and 14.05nmolBCE/L postmenopausal for NTX. The relationships between these bone turnover markers and various clinicopathological characteristics were evaluated with the chi square or Fisher's exact test. The log-rank test was used to compare relapse-free survival (RFS) in Kaplan-Meier plots. Associations of RFS were assessed with a Cox proportional-hazards model based on the results of univariate and multivariate analyses. Differences were considered statistically significant if p Results: There were significantly more 1CTP-high patients among postmenopausal women and RFS of 1CTP-high patients was significantly worse than that of 1CTP-low patients (5-year RFS: 0.65 vs 0.86; p=0.0002). Similarly, NTX-high patients were significantly associated with postmenopausal status, but there was no significant association between NTX-high worse RFS (p=0.0976). Multivariate analysis of tumor size, lymph node metastasis and nuclear grade identified 1CTP (hazard ratio: 2.04, 95% confidence interval: 1.13-3.68; p=0.018) as a significant independent prognostic factor. Subset analyses of 1CTP showed that prognosis was consistently worse recognized for postmenopausal (p=0.0002), but not premenopausal (p=0.37) patients. Furthermore, prognosis for 1CTP-high patients was worse for the estrogen receptor (ER)-positive subset (p=0.0005) but not for the ER-negative subset (p=0.22). Conclusion and discussion: High levels of serum bone resorption markers at baseline were identified as significant unfavorable prognostic factors for breast cancer patients. The prognostic significance of 1CTP seems to be prominent for postmenopausal patients with ER-positive breast cancers. These findings suggest the use of bone-modifying agents as an adjuvant therapy may be beneficial for breast cancer patients, especially for patients with high serum levels of 1CTP. Citation Format: Imamura M, Nishimikai A, Yanai A, Miyagawa Y, Higuchi T, Ozawa H, Murase K, Takatsuka Y, Miyoshi Y. High levels of serum C-terminal crosslinking telopeptide of type 1 collagen at baseline are associated with poor prognosis for breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-24.

It is speculated that adjuvant use of bisphosphonate reduces recurrence in breast cancer patients through suppression of bone resorption. To determine the prognostic impact of bone resorption markers, we investigated serum levels of the pyridinoline crosslinked carboxyterminal telopeptide of type I collagen (1CTP) and N-terminal crosslinking telopeptides of type I collagen (NTX). 1CTP and NTX were measured at baseline (before operation or neoadjuvant therapies) and afterward in 469 patients operated on breast cancer. The optimal cutoff value of 1CTP for relapse-free survival (RFS) was set at 3.6 ng/ml with an area under the receiver operating characteristics curve of 0.641 [95% confidence interval (CI) = 0.560-0.721; p = 0.0011]. However, we were unable to determine a significant cutoff value for NTX. RFS was significantly worse for 1CTP-high patients with than for those with low levels of 1CTP (p = 0.0002). Multivariate analysis with tumor size, lymph node metastasis, and nuclear grade showed that 1CTP was a significant independent prognostic factor (hazard ratio = 2.04, 95% CI = 1.13-3.68; p = 0.018). Worse prognosis for the subset with high 1CTP levels applied only to postmenopausal patients (p = 0.0002). RFS of 130 patients whose 1CTP changed from low at baseline to high at 6 months postoperatively showed RFS almost as poor as that for patients with high 1CTP throughout. These findings suggest that 1CTP may be useful not only for identifying patients with unfavorable prognosis, but also for selecting patients who may benefit from administration of bone-modifying agents in an adjuvant setting.

Residual cancer burden or Ki67 expression levels in residual tumors reportedly provided significant prognostic information for a non-pathological complete response subset after neoadjuvant chemotherapy (NAC). However, the significance of Ki67 reduction for clinical response during chemotherapy in each subtype or menopausal status is yet to be determined. A total of 183 breast cancers surgically removed after chemotherapy were recruited for this study. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki67 were determined immunohistochemically for semiquantitative measurement and these biomarkers were compared in pre- and post-NAC samples from pathological non-responders (n = 125). Responses to chemotherapy were evaluated both clinically and pathologically. Ki67 expression levels after NAC (median 5 %, range 0–70 %) were significantly reduced compared with before NAC (25, 1–80 %, P

Background Although the prognosis for operable breast cancers is reportedly worse if serum carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels are above normal, the usefulness of this prognosis is limited due to the low sensitivity and specificity; in addition, the optimal cutoff levels remain unknown. Methods A total of 1076 patients who were operated for breast cancers (test set = 608, validation set = 468) without evidence of metastasis were recruited, and their baseline and postoperative serum CEA and CA15-3 levels were analyzed. The optimal cutoff values of CEA and CA15-3 for disease-free survival (DFS) were 3.2 ng/mL and 13.3 U/mL, respectively, based on receiver operating characteristic curve and area under the curve analyses. Results The DFS of patients with high CEA levels (CEA-high: n = 191, 5-year DFS 70.6%) was significantly worse (p

Indication for chemotherapy in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers is determined on the basis of Ki67 expression level. However, since Ki67-high cancers are not necessarily sensitive to chemotherapy, identification of such patients who do not need chemotherapy is an important issue. We used immunohistochemical staining to examine the expression levels of ER, progesterone receptor (PgR), Ki67, and geminin, a marker of S to G2/M phases, in 80 ER-positive/HER2-negative breast cancers. The labeling indices of Ki67 and geminin were determined and cutoff values were set at 15 and 6 %, respectively. Ki67 and geminin expression levels were significantly associated with nuclear grade. In the Ki67-low subset, 26 out of 28 (92.9 %) cancers were geminin low and in the Ki67-high subset, 31 out of 52 (59.6 %) were geminin high. Distant disease-free survival (DDFS) of the geminin-high subset was significantly poorer than that of the geminin-low subset (P = 0.009). In the Ki67-low subset, only one patient showed recurrence. Metastasis was detected in eight out of 31 (25.8 %) patients in the geminin-high group of the Ki67-high subset, but no recurrence was observed in the geminin-low group of the Ki67-high subset. Geminin-high breast cancers are significantly associated with worse prognosis. Since poorer prognosis was recognized only in the geminin-high group in Ki67-high cancers, we speculate that geminin may be useful for identifying patients in the Ki67-high subset who can avoid unnecessary chemotherapy.

Bone-modifying agents are effective for treatment of breast cancer patients with bone metastases. Since their action is mediated through suppression of the osteoclast function, their efficacy can be determined by monitoring bone turnover markers. However, the clinical significance of these markers is yet to be compared. For this study, 52 breast cancer patients with bone metastases treated with zoledronic acid (n = 36) or denosumab (n = 22) were enrolled (6 patients were treated sequentially with both agents). Serum tartrate-resistant acid phosphatase-5b (TRACP-5b), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), N-terminal cross-linking telopeptides of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) were measured at pretreatment and 1, 3 and 6 months after treatment. Serum TRACP-5b (p

We determined the activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways in 108 cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with high and low Ki-67 expression. The expression levels of Ki-67, p53, phosphorylated MAPK (pMAPK), and protein S6 (pS6; downstream molecule of PI3K/Akt/mammalian target of rapamycin/S6 kinase pathway) were determined immunohistochemically. pS6 positivity, but not pMAPK positivity, was significantly associated with the high Ki-67 expression subset.Evaluation of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered important. Although the phosphoinositide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are thought to be involved in the luminal B subtype, the details of their contribution to breast cancer remain unclear.We determined the activation of these pathways (phosphorylated MAPK [pMAPK] and protein S6 [pS6; a downstream molecule of PI3K/Akt/mammalian target of rapamycin (mTOR)/S6 kinase (S6K)]) in 108 ER(+), HER2(-) breast cancer cases with high and low Ki-67 expression. The ER, progesterone receptor (PgR), Ki-67, p53 expression levels were also determined immunohistochemically. The cutoff value for Ki-67 was set at 15%.A significantly greater percentage of cancer cases with high Ki-67 expression showed pS6 positivity than did those with low Ki-67 expression (53.2% vs. 19.7%; P = .0003). No significant differences were found between the cases with high and low expression levels were detected for p53 (23.4% vs. 11.5%; P = .12) or pMAPK (36.2% vs. 34.4%; P = .85) positivity. Multivariate analysis showed that pS6 positivity (odds ratio 5.16, 95% confidence interval 1.95-13.63; P = .0009), nuclear grade 2 and 3, and low PgR expression (≤ 20%) were independently associated with the high Ki-67 subset.From our findings, we have concluded that the pS6 expression level is associated with the characteristics of breast cancer with high Ki-67 expression. Because these associations were observed, irrespective of menopausal status, the biologic difference seems to be less affected by estrogen signaling than by activation of S6 protein, especially in terms of proliferation. Our findings have also indicated that targeting the mTOR/S6K pathway might be a useful strategy for the treatment of ER(+)/HER2(-) breast cancer with high Ki-67 expression.

We examined the prognostic significance of progesterone receptor (PgR) expression in immunohistochemical-based luminal subtypes defined by Ki-67 expression, taking menopausal status into consideration. The study included 327 surgically removed estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancers. High Ki-67 expression (15%) and low PgR expression (£ 20%) were significant independent factors resulting in worse distant relapse-free survival. This association was observed in postmenopausalwomen but not in premenopausal women.Accurate classification of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered clinically important for determining effective adjuvant treatment. Although Ki-67 expression has been identified as an essential constituent for this classification, the role of progesterone receptor (PgR) expression has yet to be fully elucidated. Because PgR expression is influenced by the estrogen milieu, we examined the prognostic significance of PgR expression in immunohistochemical (IHC)-based luminal subtypes defined by Ki-67 expression, taking menopausal status into consideration.We examined 327 surgically removed ER(+) and HER2(-) breast cancer specimens. ER, PgR, and Ki67 expression was determined IHC for semiquantitative measurement. We used 1%, 20%, and 15% as the cutoff value for ER, PgR, and Ki-67, respectively.Breast cancer with low PgR (≤ 20%) expression was significantly associated with postmenopausal status, a large tumor size, and low ER expression. The low PgR expression subset had significantly worse distant relapse-free survival (DRFS) than the high PgR expression subset (P = .0067). This association was observed consistently in postmenopausal women but not in the premenopausal women. Multivariate analysis demonstrated that high Ki-67 expression (hazard ratio [HR], 3.80; 95% confidence interval [CI], 1.57-10.58; P = .003) and low PgR expression (HR, 2.54; 95% CI, 1.08-6.40; P = .038) were significant independent factors affecting DRFS.Low PgR expression was independently associated with a poorer prognosis for ER(+) and HER2(-) breast cancer. Determination of PgR expression combined with that of Ki-67 could thus improve the accuracy of IHC-based classification of luminal A and luminal B breast cancer, especially for postmenopausal women.

The impact of body mass index (BMI) on the risk of postmenopausal estrogen receptor (ER)-positive breast cancers has been well documented. However, the mechanism for the impact of BMI on the etiology of luminal A and luminal B subtypes has not yet been identified.We analyzed associations between BMI and breast cancers stratified by immunohistochemically defined intrinsic subtypes, and 1,297 Japanese women (615 breast cancer patients and 682 healthy women from a breast cancer screening program) were enrolled in a case-control study. ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancers were classified into luminal A and B subtypes according to Ki67 expression levels.Higher BMI was significantly positively associated with postmenopausal breast cancer risk for one-unit increase in BMI (adjusted odds ratio (aOR) 1.09, 95 % confidence interval (CI) 1.04-1.15; P = 0.0008). Analyses of postmenopausal women revealed that BMI was consistently and exclusively associated with luminal A incidence (aOR 1.18, 95 % CI 1.10-1.26; P0.0001). When BMI was divided into three categories corresponding to those of controls, among postmenopausal women, the observed positive association was confined to luminal A (high vs low, aOR 2.98, 95 % CI 1.53-5.80; P0.005), but not luminal B (aOR 0.95, 95 % CI 0.47-1.91) subtypes.We observed that BMI was significantly positively associated with increased risk of postmenopausal breast cancer for Japanese women with luminal A, but not with luminal B tumor subtype.

The aim of our study was to investigate the association of C4.4A expression in breast tumors with both patients’ clinicopathological characteristics and outcomes in order to clarify the significance of C4.4A in breast cancer. Primary breast cancer patients (n = 125, stage I–III) who had undergone breast mastectomy or breast-conserving surgery at our hospital between 2005 and 2011 were recruited for this study. Tumor samples were obtained from surgical specimens and expression status of C4.4A, estrogen receptors, progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki67 was analyzed immunohistochemically, while HER2 amplification was examined using fluorescence in situ hybridization. Multivariate analysis showed that HER2 positivity was the only independent predictive factor for C4.4A expression (odds ratio 5.31, 95 % confidence interval 2.04–15.72; P

High body mass index (BMI) is associated not only with a higher incidence of breast cancers but also with poorer prognosis. It is speculated that both enhanced production of estrogens and other factors associated with obesity are involved in these associations, but the biological characteristics associated with high BMI have yet to be thoroughly identified. We studied 525 breast cancers, focusing on biological differences between tumors associated with high and low BMI and by immunohistochemically defined intrinsic subtype. Ki67 expression levels were used to differentiate luminal A from luminal B estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)-breast cancers. Premenopausal patients with high BMI showed a significantly higher frequency of lymph node metastasis (46.4 % vs. 22.9 %, P = 0.005) and tended to have a larger tumor size (P = 0.05) and higher nuclear grade (P = 0.07) than those with low BMI. These differences were not observed among postmenopausal patients. BMI was not associated with distribution of breast cancer subtypes, and ER, progesterone receptor (PR), and Ki67 expression levels of each subtype showed no differences between high and low BMI among premenopausal patients. Higher BMI might influence aggressive tumor characteristics among premenopausal patients, but its influence on ER, PR, and Ki67 expression levels seems to be limited.

Estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers can be divided into luminal A and luminal B subtypes based on Ki67 expression levels. However, the biological differences in ER and progesterone receptor (PR) expression levels between these luminal subtypes are not clear.We examined immunohistochemical expression levels of ER, PR, and Ki67 in 180 ER-positive/HER2-negative breast cancers while taking menopausal status into account. Breast cancers were divided according to ER and PR levels (H:50%, L: ≤ 50%), and luminal A and B were classified by the Ki67 labeling index (A: Ki6714%, B: Ki67 ≥ 14%).When breast cancers were classified based on ER and PR levels, the distribution of pre- and postmenopausals was significantly different for luminal A (P0.0001), but not for luminal B cancers. As for luminal A, ER-H/PR-L cancers were rare among premenopausals (8%), but frequent among postmenopausals (54%). Correlation between ER and PR levels among luminal A cancers was strong in premenopausals but weak in postmenopausals. Since crosstalk with growth factor signaling is unlikely in luminal A, we speculate that intratumoral estrogen insufficiency contributed to the characteristics of postmenopausal ER-H/PR-L cancers.We speculate that the biological characteristics of luminal A cancers are influenced by the estrogen environment, but its influence on luminal B cancers may be limited. We believe these considerations constitute useful information for a better understanding of the biology of ER-positive-HER2-negetive breast cancers.