Response-Guided Omission of Anthracycline in Patients with HER2-Positive Early Breast Cancer Treated with Neoadjuvant Taxane and Trastuzumab: 5-Year Follow-Up of Prognostic Study Using Propensity Score Matching.

BACKGROUND: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). RESULTS: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. CONCLUSIONS: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.

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.

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel.

BACKGROUND: Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). METHODS: Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/µL, 2, and 250, respectively. RESULTS: PFS was significantly improved in patients with ALC ≥1500/µL compared to those with ALC 1000-, <1500/µL or ALC < 1000/µL (P = 0.0106). High baseline ALC was significantly associated with improved PFS (≥1500/µL; hazard ratio [HR]: 0.3715; 95% confidence interval [CI]: 0.1735-0.7955; P = 0.0108). In contrast, improved PFS was not significantly associated with NLR or PLR. Improved PFS in patients with ALC ≥1500/µL was observed irrespective of visceral metastasis or chemotherapy regimen. CONCLUSIONS: Our results showed that baseline ALC was a predictive factor for PFS in HER2-positive ABC treated with PT irrespective of combined chemotherapy regimen. Anti-tumor effects might be mediated not only by the tumor microenvironment, but also by systemic peripheral circulating lymphocytes. Baseline systemic parameters such as peripheral lymphocyte count might be beneficial in addition to disease extent for predicting the efficacy of PT treatment. TRIAL REGISTRATION: UMIN000012375 , registration date: 21NOV2013, and UMIN000006838 , registration date: 6DEC2011.

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.

Independent prognostic impact of preoperative serum carcinoembryonic antigen and cancer antigen 15-3 levels for early breast cancer subtypes.

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 < 0.0001) than that of CEA-low patients (n = 885, 5-year DFS 87.2%). There was a significant difference in DFS (p < 0.0001) between CA15-3-high and CA15-3-low patients (n = 314 and n = 762, respectively; 5-year DFS 71.8 vs. 89.3%). Significant associations between DFS and CA15-3 levels were observed irrespective of the subtypes. Multivariable analysis indicated that tumor size, lymph node metastasis, tumor grade, and CEA (p = 0.0474) and CA15-3 (p < 0.0001) levels were independent prognostic factors (hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.005-2.245 for CEA; HR 2.088, 95% CI 1.457-2.901 for CA15-3). CONCLUSIONS: These findings suggest that CEA and CA15-3 levels might be useful for predicting the prognosis of patients with operable early breast cancer irrespective of the subtype. Serum levels at baseline may reflect tumor characteristics for metastatic potential even when these levels are within the normal ranges.

Impact of biomarker changes during neoadjuvant chemotherapy for clinical response in patients with residual breast cancers.

BACKGROUND: 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. METHODS: 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. RESULTS: Ki67 expression levels after NAC (median 5 %, range 0-70 %) were significantly reduced compared with before NAC (25, 1-80 %, P < 0.0001), but only in patients who attained clinical response. This significant suppression of Ki67 in clinical responders was consistently observed in breast cancers from the ER-positive subset, but not the ER-negative subset in the total test set (n = 120). These observations were also made in the validation set (n = 63). Among premenopausal, but not postmenopausal patients, a significant decrease in PgR expression levels was detected in breast cancers of patients who attained clinical response (pre-NAC 50, 0-100 %, post-NAC 5, 0-20 %; P = 0.0003). CONCLUSION: The impact of Ki67 suppression on clinical response seems to be restricted to ER-positive breast cancers. Since PgR expression levels of premenopausal ER-positive cancers were significantly reduced in clinical responders, inhibition of estrogen signaling due to chemotherapy-induced amenorrhea may be involved in this association.

High levels at baseline of serum pyridinoline crosslinked carboxyterminal telopeptide of type I collagen are associated with worse prognosis for breast cancer patients.

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.

Influence of body mass index on clinicopathological factors including estrogen receptor, progesterone receptor, and Ki67 expression levels in breast cancers.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Higher BMI might influence aggressive tumor characteristics among premenopausal patients, but its influence on ER, PR, and Ki67 expression levels seems to be limited.

Pembrolizumab response in stage IV luminal-type breast cancer with high microsatellite instability: a case report.

BACKGROUND: Pembrolizumab (PEM), an immune checkpoint inhibitor (ICI), is often used for triple-negative breast cancer, but can also be used to treat solid tumors that exhibit high microsatellite instability (MSI-High). However, patients with breast cancer rarely have MSI-High, the use of PEM in such cases in clinical practice is uncertain due to lack of sufficient supporting data. Here, we report the case of a premenopausal woman in who received PEM for MSI-High luminal-type breast cancer. CASE PRESENTATION: A 40-year-old premenopausal Asian woman was diagnosed with stage IIA (T2N0M0) breast cancer and had an Oncotype DX recurrence score of 38. After surgery, she received 4 courses of chemotherapy with docetaxel and cyclophosphamide. After 3 months of tamoxifen therapy, the patient complained of abdominal pain due to right iliac metastasis, and biopsy of the metastatic lesion showed of luminal type; she was sequentially treated with fulvestrant, a CDK4/6 inhibitor, and an anticancer drug (TS1), but over the next year, metastasis to the bone and para-aortic lymph nodes increased. Tumor was MSI-High; PEM was started, and after three courses, bone metastases were reduced, para-aortic lymph node metastases resolved, opioids were discontinued, and the patient returned to society; PEM was administered for 1 year with no worsening of bone metastases on imaging. Asymptomatic brain metastasis less than 1 cm was detected and gamma knife was performed. Six months after completion of PEM, the patient is working with no new lesions. CONCLUSION: We report a case of luminal-type breast cancer with bone metastases and MSI-High, which was treated with PEM and showed a rapid therapeutic response.

A case of pathological complete response of advanced rectal cancer to preoperative chemoradiotherapy using S-1.

In patients with advanced rectal cancer, preoperative chemoradiotherapy is superior to postoperative chemoradiotherapy because of causing less toxicity and achieving higher rates of sphincter preservation and curative resection. We treated a patient who had advanced rectal cancer with preoperative chemotherapy using S-1 and concurrent radiotherapy. S-1 was orally administered at a dose of 100 mg/day during the first cycle (two-week on and one week off). During the third cycle, radiotherapy was initiated concurrently and a total dose of 45 Gy was given. The most severe adverse event was grade 3 leukopenia during the third cycle. On day 42 after completing radiotherapy, low anterior resection with diverting colostomy was performed. Histological examination found no viable cancer cells in the resected specimens, including the primary tumor site and lymph nodes. Thus, a pathological complete response was achieved. Postoperatively, anastomotic leakage occurred, but it was resolved with transanal drainage. Preoperative chemoradiotherapy using S-1 contributed to sphincter preservation and curative resection in this patient. This regimen was both effective and well-tolerated, suggesting that it could be useful for advanced rectal cancer.

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.

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.

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.

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.

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.

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.

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.

Frequent downregulation of LRRC26 by epigenetic alterations is involved in the malignant progression of triple-negative breast cancer.

Triple-negative breast cancer (TNBC), defined as breast cancer lacking estrogen- and progesterone­receptor expression and human epidermal growth factor receptor 2 (HER2) amplification, is a heterogeneous disease. RNA-sequencing analysis of 15 TNBC specimens and The Cancer Genome Atlas-TNBC dataset analysis identified the frequent downregulation of leucine-rich repeat-containing 26 (LRRC26), which negatively regulates nuclear factor-κB (NF-κB) signaling, in TNBC tissues. Quantitative polymerase chain reaction and bisulfite pyrosequencing analyses revealed that LRRC26 was frequently silenced in TNBC tissues and cell lines as a result of promoter methylation. LRRC26 expression was restored by 5-aza-2'-deoxycytidine (5'-aza-dC) treatment in HCC1937 TNBC cells, which lack LRRC26 expression. Notably, small interfering RNA-mediated knockdown of LRRC26 expression significantly enhanced the anchorage-independent growth, invasion and migration of HCC70 cells, whereas ectopic overexpression of LRRC26 in BT20 cells suppressed their invasion and migration. Conversely, neither knockdown nor overexpression of LRRC26 had an effect on cell viability in the absence of tumor necrosis factor-α (TNF-α) stimulation. Meanwhile, overexpression of LRRC26 caused the reduction of TNF-α-mediated NF-κB luciferase reporter activity, whereas depleting LRRC26 expression resulted in the upregulation of TNF-α-mediated NF-κB downstream genes [interleukin-6 (IL-6), IL-8 and C-X-C motif chemokine ligand-1]. Taken together, these findings demonstrate that LRRC26 is frequently downregulated in TNBC due to DNA methylation and that it suppresses the TNF-α-independent anchorage-independent growth, invasion and migration of TNBC cells. Loss of LRRC26 function may be a critical event in the aggressiveness of TNBC cells through a TNF-α/NF-κB-independent mechanism.

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.

Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases.

BACKGROUND: 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. METHODS: 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. RESULTS: Serum TRACP-5b (p < 0.0001), NTX (p = 0.0007) and BAP (p = 0.0032) decreased significantly after treatment. The baseline median value of TRACP-5b (457.5 mU/dL, range 173-1630 mU/dL) decreased to 137 mU/dL (91-795 mU/dL) 1 month after treatment. Reduction in serum NTX and BAP was greatest after 3 and 6 months, respectively. TRACP-5b, NTX and BAP were above normal levels at baseline in 62.5, 25 and 35.3 % of patients, respectively, and nearly 80 % of these patients attained normal levels during the treatment. CONCLUSIONS: Although bone-modifying agents reduced the baseline levels of TRACP-5b, NTX and BAP significantly, the reduction patterns differed. TRACP-5b appears to affect levels most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings suggest that the efficacy of TRACP-5b is clinically significant when considering which bone-modifying agents to use for breast cancer patients with bone metastases.