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Background: The usefulness of prophylactic surgery and surveillance for hereditary breast cancer has been demonstrated, and germline testing for BRCA1 and BRCA2 had been covered by insurance since 2020 in Japan. In addition to BRCA1 and BRCA2, several other genes are also associated with an increased risk of developing breast cancer, such as PALB2, ATM, BARD1, CHEK2, PTEN, and TP53. Next-generation sequencing-enabled multigene panel tensing provides information about these gene variants at the same time, and at a low cost. Although germline testing of BRCA1 and BRCA2 has become widespread in Japan, multi-panel gene testing for germline variants has been conducted only in a limited number of facilities, partly due to the difficulty associated with dealing with the gene variant information obtained from the test. The aim of this study was to clarify the current status of multigene panel testing in our institute, and reveal the characteristics of the variants detected in patients with, or predisposed to, hereditary breast cancer. Methods: This retrospective study included 37 individuals who underwent next-generation sequencing-based multigene panel testing in order to investigate any inherited genetic variants due to a suspicion of hereditary breast cancer. Eighteen patients had a diagnosis of breast cancer with a family history of breast and/or ovarian cancer, nine patients had a diagnosis of breast cancer without family history of breast or ovarian cancer, and 10 patients had a family history of breast cancer but had not developed breast cancer themselves. Results: Utilizing mutigene panel testing, at least one alteration was found in 24 genes, and a total of 39 variants were found in the 37 patients. Of these 37 patients, nine (24.3%) had a pathogenic/likely pathogenic variant with or without other variants of uncertain significance (VUS), 15 (40.5%) had VUS, and 13 (35.1%) had negative genetic test results. Among the nine patients with pathogenic/likely pathogenic variants, seven had variants in either BRCA1 or BRCA2 (one BRCA1 pathogenic variant, five BRCA2 pathogenic variants, and one BRCA2 likely pathogenic variant), while the remaining positive results were attributed to other genes (one MLH1 pathogenic variant, and one SDHB pathogenic variant). VUS included BRCA1 and BRCA2, as well as other breast cancer-associated genes, such as ATM (n=2), CDH1 (n=2), NF1 (n=2), PALB2 (n=1), CHEK2 (n=1), NBN (n=1), and RAD51D (n=1). VUS also included other cancer syndrome-related genes, such as MLH1 (n=2), MUTYH (n=2), APC (n=1), and RET (n=1). Conclusion: Multigene panel tests in our institute revealed pathogenic/likely pathogenic variants in 24.3% of individuals who suspected hereditary breast cancer. As expected, multigene panel tests also revealed more VUS than pathogenic variants and 40.5% individuals were detected with VUS, which included many genes associated with hereditary breast cancer and other cancer syndromes, in addition to BRCA1 and BRCA2. Individuals with VUS will need to cope with new information if the interpretation of the variant changes in the future. We need to be aware of the characteristics and limitations of this type of panel testing, and to properly utilize the test results and information obtained for good quality patient care. Citation Format: Yusa Atake, Masayuki Nagahashi, Haruka Kanaoka, Akira Hattori, Ayako Bun, Reiko Fukui, Hiromi Ozawa, Yukie Fujimoto, Tomoko Higuchi, Michiko Imamura, Keiko Murase, Yuichi Takatsuka, Mina Kashima, Chiho Okada, Chinatsu Kinjo, Mikako Miyata, Ayako Miyazaki, Mako Ueda, Hiroshi Tsubamoto, Hideaki Sawai, Yasuo Miyoshi. Germline variants detected by next-generation sequencing-based multigene panel testing in patients with suspected hereditary breast cancer at a University Hospital in Japan [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-12-02.

Endocrine therapy (ET) with or without CDK4/6 inhibitors is the primary treatment choice for patients with estrogen receptor (ER)-positive and HER2-negative subtype of metastatic breast cancer (MBC). We examined the metabolic parameters identified usingWe included 136 patients with MBC treated with ET alone (n=107) or combined with CDK4/6 inhibitor (n=29) and examined using FDG-PET before treatment began. The highest maximum value of the standard uptake value (SUVmax), whole-body metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated.Progression-free survival (PFS) was significantly longer in patients with low levels of MTV, TLG, and SUVmax than those with higher levels (median PFS 49.5 vs. 20.7 months, p=0.001 for MTV, 49.5 vs. 20.7 months, p=0.0016 for TLG, 37.0 vs. 20.7 months, p=0.012 for SUVmax). Multivariable analysis revealed that TLG (hazard ratio=6.383, 95% confidence interval=1.167-34.913, p=0.033) was independently and significantly associated with PFS. The relationship between TLG levels and PFS was significant in patients treated with ET with (p=0.0054) and without (p=0.0188) CDK4/6 inhibitor.TLG at baseline was a significant predictor for sensitivity to ET alone or combined with CDK4/6 inhibitor. These data may be useful to identify patients that would benefit from ET.

The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer treated with the CDK4/6 inhibitors, abemaciclib and palbociclib.A total of 83 patients treated with fulvestrant plus abemaciclib or palbociclib were included in this study. Progression-free survival (PFS) and overall survival (OS) were compared in relation to baseline levels of ALC, NLR, PLR and CRP.The cut-off values of ALC, NLR, PLR, and CRP for PFS were determined from the receiver operating characteristic curve using the Youden index for area under the curve and set at 1,212/μl, 1.964, 170 and 0.220 mg/dl, respectively. In the abemaciclib-treated group, ALC-high patients showed significantly better PFS than ALC-low patients (p=0.0151) and multivariate analysis revealed that ALC was an independent prognostic factor for PFS (p=0.0085). In the palbociclib-treated group, there was no significant relationship between any peripheral blood biomarkers and PFS. In both treatment groups, ALC-high patients showed significantly better OS than ALC-low patients (p=0.0169 and 0.0290, respectively). Multivariate analysis revealed ALC was an independent prognostic factor for OS in both abemaciclib- and palbociclib-treated groups (p=0.0112 and 0.0202, respectively).ALC is an independent prognostic factor for estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer patients treated with the CDK4/6 inhibitors abemaciclib and palbociclib.

Background The reason for the poor prognosis of estrogen receptor (ER) + /human epidermal growth factor receptor 2 (HER2)− breast cancer patients with high levels of tumor-infiltrating lymphocytes (TILs) is poorly understood. The association between TILs and response to neoadjuvant endocrine therapy (NET) was examined. Methods We recruited 170 patients with ER + /HER2− breast cancer who were treated with preoperative endocrine monotherapy. TILs were evaluated before and after NET, and their changes were noted. Furthermore, T cell subtypes were examined using CD8 and FOXP3 immunohistochemical analyses. Neutrophil and lymphocyte counts in the peripheral blood were analyzed with reference to TIL levels or changes. Responders were defined as Ki67 expression levels ≤ 2.7% after treatment. Results Post-treatment (p = 0.016), but not pre-treatment (p = 0.464), TIL levels were significantly associated with the response to NET. TIL levels increased significantly after treatment among non-responders (p = 0.001). FOXP3 + T cell counts increased significantly after treatment in patients with increased TILs (p = 0.035), but not in those without increased TILs (p = 0.281). Neutrophil counts decreased significantly after treatment in patients without increased TILs (p = 0.026), but not in patients with increased TILs (p = 0.312). Conclusion An increase in TILs after NET was significantly associated with a poor response to NET. Given that FOXP3 + T-cell counts increased, and neutrophil counts did not decrease in patients with increased TILs after NET, the induction of an immunosuppressive microenvironment was speculated to play a role in the inferior efficacy. These data might partially indicate the involvement of the immune response in the efficacy of endocrine therapy.

To investigate the relationship between fluorodeoxyglucose (FDG) uptake (maximum standardised uptake value [SUVmax]) and immune markers (tumour-infiltrating lymphocytes [TILs] and neutrophil-to-lymphocyte ratio [NLR]) and evaluate the potential prognostic value of any correlations.Data from 502 patients with breast cancer, including 346 oestrogen receptor (ER)-positive / human epidermal growth factor receptor 2 (HER2)-negative, 88 HER2-positive, and 68 triple-negative cases, who had undergone surgery were reviewed. Relationships between the clinicopathological factors, SUVmax, TILs, NLR, recurrence-free survival (RFS), and overall survival of all patients and each subtype were evaluated using a Cox proportional hazards model and log-rank test. A sub-analysis of patients divided into low and high TIL groups was also undertaken.High SUVmax was significantly related to high TILs (p 0.0001). In low TIL (TILs1) group, patients with high SUVmax (≥3.585) had a significantly shorter RFS than those with low SUVmax (3.585; p 0.0001). In high TIL (TILs2,3) group, patients with high SUVmax had a shorter RFS than those with low SUVmax without a significant difference (p = 0.35). Multivariate analysis of 502 patients showed high SUVmax, high T status, and nodal metastasis were independent negative predictors of RFS. In 317 TILs-low patients, high SUVmax, high T status, nodal metastasis, and ER-positivity were independent predictors of RFS. In 185 TILs-high patients, nodal metastasis was an independent predictor of RFS. In ER-positive/HER2-negative and HER2-positive subtypes, SUVmax was a significant predictive parameter in the TILs-low but not TILs-high groups.FDG uptake may be predictive of immunological features and aggressive features in breast cancer patients.

(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.

Background/aim Interleukin (IL)-18, which belongs to the IL-1 superfamily of cytokines, is a known interferon-gamma (IFN-γ)-inducing factor. Since IFN-γ plays an essential role in anticancer immunity mediated through cytotoxic T cells, IL-18 may also contribute to the function of immunosurveillance. The aim of the study was to examine the association of IL-18 with the outcomes of patients with breast cancer. Patients and methods Serum IL-18 levels were determined at baseline in 270 patients operated for breast cancer, and the relapse-free survival (RFS) was compared between IL-18-high and -low groups. The relationships between IL-18 and tumor-infiltrating lymphocytes (TILs) or the neutrophil-to-lymphocyte ratio (NLR) were also investigated. Results The RFS of patients was significantly better in the IL-18-low group than in the IL-18-high group (p=0.032). According to the multivariate analysis, IL-18 was a significant and independent predictive factor for RFS (hazard ratio(HR)=0.336; 95% confidence interval(CI)=0.147-0.727; p=0.0053). No association was observed between the IL-18 levels and TILs or NLRs. Conclusion IL-18 levels may be useful for predicting the prognosis of patients who have received surgical treatment for breast cancer.

The usefulness of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography for evaluating the treatment efficacy of breast cancers is well-established; however, the predictive values of parameters such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) remain unknown. This study examined 199 breast cancers treated with primary systemic chemotherapy (PSC) followed by operation, and determined the values of maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), MTV, and TLG at baseline. Among these cases, data on early changes in these metabolic parameters in 70 breast cancers were also assessed. A pathological complete response (pCR) was achieved in 64 breast cancers. Breast cancers with low MTV at baseline had a significantly higher pCR rate than breast cancers with high MTV (47.9% vs. 23.4%; p = 0.0005). High reduction rates (∆) of SUVmax (p = 0.0001), SUVpeak (p = 0.0001), and SUVmean (p

(Background) SUVmax levels (maximum radioactivity concentration per a pixel) on FDG-PET reflect glucose uptake and it is clinically useful as a prognostic factor. It is reported that breast cancer with high levels of SUVmax causes insufficient glucose concentration in stromal tissue, which results in suppressed cytotoxic T-lymphocytes function. These data may indicate that the prognostic significance of SUVmax levels is influenced by local immune environment of breast cancer. The aim of this study is to investigate whether local immune responses of breast cancer affect correlation of SUVmax levels and prognosis. (Method) The 278 invasive breast cancer patients were recruited who underwent surgery at Hyogo College of Medicine Hospital and whose SUVmax levels in the breast were examined before surgery or neo-adjuvant therapy. The cutoff value of SUVmax levels was set at 3.585. Tumor infiltrate lymphocytes (TILs) were evaluated as a local immune response and the distributions of TILs were divided into three groups, inflamed (intra-tumoral lymphocytes, Inf), immune excluded (peri-tumoral lymphocytes, IE) and immune desert (very few lymphocytes, ID). During follow-up period (median 39 months), 21 patients relapsed. (Results) Relapse free survival (RFS) in the SUVmax-high group was significantly worse than in the SUVmax–low group (p=0.0026). There was no correlation between TILs distribution patterns and RFS. In the IE+ID group (175 patients) SUVmax levels were not correlated with prognosis, but in the Inf group (103 patients) RFS of SUVmax-high was significantly worse than of SUVmax-low (p=0.0051). In the multivariate analysis including nodal status and nuclear grade, SUVmax levels of the Inf group was an independent prognostic factor. (Discussion and conclusion) SUVmax levels in primary lesions were correlated with prognosis only in the Inf group and were not in the IE+ID group. A significance of SUVmax levels as a prognostic factor may be diverse depending on the local immune environment of breast cancer. A novel therapeutic strategy such as inducing suppression of glucose uptake in cancer cells is suggested for breast cancer with immune inflamed. Citation Format: Fujimoto Y, Higuchi T, Watanabe T, Hida AI, Imamura M, Kitajima K, Miyoshi Y. A significance of SUVmax levels on FDG-PET as a prognostic factor may be mediated by local immune environment of breast cancer [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 P2-08-35.

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 (

Background/aim Patients with non-luminal breast cancer subtypes with high levels of tumor infiltrating lymphocytes (TILs) have better prognosis than those with luminal subtype. We evaluated the role of TILs according to the subtype. Materials and methods An immunohistochemical analysis of 139 breast cancer cases was conducted to calculate the FOXP3+/CD8+ T cell ratios and their relationships with TILs and disease-free survival (DFS) were evaluated. Results FOXP3+/CD8+ T cell ratios were significantly associated with TIL levels only in luminal breast cancers (p=0.0001). Low FOXP3+/CD8+ T cell ratio was significantly associated with longer DFS (p=0.017). All luminal subtype patients with high TIL levels had high FOXP3+/CD8+ T cell ratios compared to only half of non-luminal subtype patients with high TIL levels. Conclusion High FOXP3+/CD8+ T cell ratios in breast cancers may partly explain the worse prognosis of luminal breast cancers, but not that of non-luminal breast cancers with high TIL levels.

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: 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.

Analysis of anticancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C‐C motif chemokine ligand 5 (CCL5), which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead‐based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease‐free survival (DFS) of patients with high CCL5 levels (cut‐off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10‐0.39; P, We found that high levels of serum C‐C motif chemokine ligand 5 (CCL5), a chemokine produced by immune cells, were significantly associated with improved prognosis of patients with operated breast cancer. As the relative expression of mRNA CCL5 was elevated in stromal cells, serum CCL5 seems to be derived not from cancer cells, but from stromal cells. CCL5 might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms.

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 The usefulness of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography for evaluating the treatment efficacy of breast cancers is well-established; however, the predictive values of parameters such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) remain unknown. Methods This study examined 199 breast cancers treated with primary systemic chemotherapy (PSC) followed by operation, and determined the values of maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), MTV, and TLG at baseline. Among these cases, data on early changes in these metabolic parameters in 70 breast cancers were also assessed. Results A pathological complete response (pCR) was achieved in 64 breast cancers. Breast cancers with low MTV at baseline had a significantly higher pCR rate than breast cancers with high MTV (47.9% vs. 23.4%; p = 0.0005). High reduction rates (∆) of SUVmax (p = 0.0001), SUVpeak (p = 0.0001), and SUVmean (p

The estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki67 are biomarkers for early breast cancer. These markers are usually examined by immunohistochemistry (IHC), and positive is defined as more than 1％ for ER or PgR, and a score of 3+ or 2+ with in situ hybridization positivity for HER2. Indications for endocrine therapy and anti-HER2 therapy are determined according to these cutoff values. These markers are also clinically useful for classifying IHC-based subtypes. Although a cutoff value for Ki67 has yet to be determined, ER-positive/HER2-negative breast cancer is further divided into luminal A or B using Ki67 and PgR expression levels. In addition, multigene assays are clinically available to assess the indications for chemotherapy. Since a discordance in biomarkers between primary and metastatic cancer occurs in some cases, rebiopsy is recommended. It is also important to take measures to ensure the accuracy of IHC procedures because the results can easily be affected by a number of factors. The appropriate treatment should be selected by taking the clinical significance of these biomarkers into consideration.

The efficacy of trastuzumab emtansine (T-DM1) is prolonged for some patients; however, the predictive factors remain unknown. We focused on a peripheral blood biomarker, the neutrophil-to-lymphocyte ratio (NLR), regarding T-DM1 treatment efficacy. 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 and after one cycle. The cutoff value of the NLR was set at median value 2.56. The progression-free survival (PFS) of patients with NLR-low at baseline (n = 26; median, not reached) was significantly better than that of patients with NLR-high (n = 27; median, 4.13 months; hazard ratio [HR], 0.226; 95% confidence interval [CI], 0.112–0.493; p = 0.0001). Longer overall survival was significantly associated with a low NLR (HR, 0.384; 95% CI, 0.170–0.910; p = 0.0296). In the subgroup analysis, patients with NLR-low consistently had longer PFS compared to those with NLR-high irrespective of the number of prior chemotherapy regimens, prior trastuzumab, visceral metastasis, estrogen receptor status, and human epidermal growth factor receptor 2 (HER2) score. Although detailed mechanisms remain unknown, treatment efficacy of T-DM1 may be partly mediated by activation of the immune system. Low baseline NLR appears to be beneficial for treatment with T-DM1 in HER2-positive breast cancers.

The therapeutic effect of systemic treatment for breast cancer (BC) generally depends on its intrinsic subtypes. In addition, tumor infiltrating lymphocytes (TILs) are considered to be an independent factor for tumor shrinkage and disease prognosis. High TILs at baseline or after primary systemic chemotherapy are reported to be associated with better survival in triple-negative or human epithelial growth factor receptor 2 (HER2)-positive BCs. However, the prognostic value of TILs in estrogen receptor (ER)-positive and HER2-negative (ER+/HER2−) BC is still controversial. We assessed TIL score (low, intermediate, and high) before and after primary systemic chemotherapy in every subtype of BC, and compared the clinical outcomes. Biopsy specimens of 47 triple-negative, 58 HER2+ and 91 ER+/HER2− BCs were used to assess TILs before treatment. To assess TILs after treatment, we examined residual invasive carcinoma in surgically resected samples of 28 triple-negative, 30 HER2+ and 80 ER+/HER2− BCs. A high TIL score in triple-negative BC before treatment resulted in a significantly higher proportion of pathological complete response (pCR). In contrast, ER+/HER2− BC exhibited fewer instances of pCR than other subtypes. Although not statistically significant, ER+/HER2− cases with a high TIL score also tended to achieve pCR (p = 0.088). Moreover, we revealed that low TIL BCs after chemotherapy, but not at baseline, had significantly better relapse-free survival in ER+/HER2− BC (p = 0.034). Pathological examination of TILs after treatment may be a surrogate marker for prognosis in ER+/HER2− BC.

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

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