Baseline interleukin-6 is a prognostic factor for patients with metastatic breast cancer treated with eribulin.

PURPOSE: Eribulin is a unique anti-cancer drug which can improve overall survival (OS) of patients with metastatic breast cancer (MBC), probably by modulating the tumor immune microenvironment. The aim of this study was to investigate the clinical significance of serum levels of immune-related and inflammatory cytokines in patients treated with eribulin. Furthermore, we investigated the association between cytokines and immune cells, such as myeloid-derived suppressor cells (MDSCs) and cytotoxic and regulatory T cells, to explore how these cytokines might affect the immune microenvironment. METHODS: Sixty-eight patients with MBC treated with eribulin were recruited for this retrospective study. The relationship of cytokines, including interleukin (IL)-6, to progression-free survival and OS was examined. CD4+ and CD8+ lymphocyte, MDSCs and regulatory T cell levels were determined in the blood by flow cytometry analysis. RESULTS: In our cohort, patients with high IL-6 at baseline had shorter progression-free survival and OS compared with those with low IL-6 (p = 0.0017 and p = 0.0012, respectively). Univariable and multivariable analyses revealed that baseline IL-6 was an independent prognostic factor for OS (p = 0.0058). Importantly, CD8+ lymphocytes were significantly lower and MDSCs were significantly higher in patients with high IL-6, compared to those with low IL-6. CONCLUSION: Baseline IL-6 is an important prognostic factor in patients with MBC treated with eribulin. Our results show that high IL-6 is associated with higher levels of MDSCs which suppress anti-tumor immunity, such as CD8+ cells. It appears that eribulin is not particularly effective in patients with high IL-6 due to a poor tumor immune microenvironment.

Total Lesion Glycolysis Levels as Predictive Indicators in Patients With Metastatic and Recurrent Breast Cancer Undergoing Endocrine Therapy With or Without CDK4/6 Inhibitor.

BACKGROUND/AIM: 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 using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in terms of sensitivity, since no predictive factors exist. PATIENTS AND METHODS: We 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. RESULTS: 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. CONCLUSION: 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.

Absolute Lymphocyte Count Is an Independent Prognostic Factor for ER-positive HER2-negative Advanced Breast Cancer Patients Treated With CDK4/6 Inhibitors.

BACKGROUND/AIM: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

C-Reactive Protein and Absolute Lymphocyte Count Can Predict Overall Survival of Patients Treated With Eribulin.

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.

Prognostic Significance of Neutrophil-to-lymphocyte Ratio in Luminal Breast Cancers With Low Levels of Tumour-infiltrating Lymphocytes.

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 (<10%), intermediate (≥10 to <50%), and high (≥50%). RESULTS: Recurrence-free survival (RFS) was significantly longer in patients with low NLR (n=459) than in those with high NLR (n=218) (p=0.0383). In ER-positive/HER2-negative and TIL-low breast cancers, there were significant associations between NLR levels and RFS (p=0.0129) or overall survival (OS) (p=0.0046). On multivariate analysis, NLR was a significant and independent factor for OS (hazard ratio=3.78; 95% confidence interval=1.21-14.17; p=0.022). CONCLUSION: These data may be useful for predicting patient prognosis and understanding the clinical significance of immune status in breast cancers.

Association Between FOXP3/CD8 Lymphocyte Ratios and Tumor Infiltrating Lymphocyte Levels in Different Breast Cancer Subtypes.

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.

Baseline neutrophil-to-lymphocyte ratio and c-reactive protein predict efficacy of treatment with bevacizumab plus paclitaxel for locally advanced or metastatic breast cancer.

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.

A Single-centre, Retrospective, Observational Analysis of Fulvestrant for Recurrent/metastatic Breast Cancer According to Metastatic Site.

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.

Prognostic significance of tumor-infiltrating lymphocytes may differ depending on Ki67 expression levels in estrogen receptor-positive/HER2-negative operated breast cancers.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Significance of Metabolic Tumor Volume at Baseline and Reduction of Mean Standardized Uptake Value in 18F-FDG-PET/CT Imaging for Predicting Pathological Complete Response in Breast Cancers Treated with Preoperative Chemotherapy.

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 < 0.0001) resulted in an increased pCR compared with those for low ∆. The pCR rate was highest for the combination of low MTV and high ∆SUVmean (86.7%), and lowest for high MTV and low ∆SUVmean (15.4%); the remaining combinations were intermediate (58.6%; p < 0.0001). The combination of low MTV at baseline and high ∆SUVmean was a significant and independent predictor for pCR (odds ratio 28.63; 95% confidence interval 1.94-422.42; p = 0.0146) in multivariable analysis. CONCLUSIONS: Low levels of MTV at baseline and a high reduction of SUVmean after PSC was significantly associated with pCR. These findings suggest the usefulness of these metabolic parameters for predicting the treatment efficacy of breast cancers.

Significance of baseline neutrophil-to-lymphocyte ratio for progression-free survival of patients with HER2-positive breast cancer treated with trastuzumab emtansine.

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.

Improved prognosis of low baseline neutrophil-to-lymphocyte ratio is significantly exclusive in breast cancer patients with high absolute counts of lymphocytes.

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<0.0001) subgroup (n=355), but not in the NLR-low, ALC-low (≤1,688/µl; 5-year RFS, 0.87 vs. 0.87; P=0.46) subgroup (n=534). Using multivariate analysis, NLR was observed to be a significant and independent factor for RFS (hazard ratio: 3.52; 95% confidence interval: 1.61-7.32; P=0.0023) in the ALC-high breast cancer subgroup. Prognostic significance for baseline NLR was found exclusively in the ALC - high subgroup. Since NLR is a simple marker, the results obtained here might be useful for identifying patients who have high recurrence risk, and those that are candidates for additional treatments.

High levels of serum CA15-3 and residual invasive tumor size are associated with poor prognosis for breast cancer patients with non-pathological complete response after neoadjuvant chemotherapy.

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.

Significant Association Between Low Baseline Neutrophil-to-Lymphocyte Ratio and Improved Progression-free Survival of Patients With Locally Advanced or Metastatic Breast Cancer Treated With Eribulin But Not With Nab-Paclitaxel.

INTRODUCTION: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.