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(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.