Significance of MUC1 and ß-Catenin Localization in Mucinous Carcinoma of the Breast.

BACKGROUND/AIM: There are two main subtypes of mucinous carcinoma (MC) based on the quantification of the mucinous component: the pure variant (pMC) and the mixed variant (mMC). pMC has been subdivided into pure A with a hypocellular variant, and pure B with a hypercellular variant. PATIENTS AND METHODS: We retrospectively analyzed the clinicopathological features of 99 patients with MC who were treated at our institution from January 2002 to December 2014. We evaluated the expression profiles of markers, including mucin (MUC) family members, in the patients groups representing different MC subtypes by performing immunohistochemistry to identify factors involved in the differentiation and progression of MCs. RESULTS: Among the 99 patients, 76 (76.8%) had pure mucinous carcinomas (pMC) and the other 23 (23.2%) had mixed mucinous carcinomas (mMC). Of the pMCs, 54 were pure A and 22 were pure B. The prognosis was worse for pure B than pure A and worse for mMC than pMC. Although there was no significant difference in clinicopathological factors between the pure A and pure B groups, immunohistochemical staining revealed differences in the localization of mucin MUC1 and ß-catenin. A comparison of the pMC and mMC cases revealed more lymphovascular invasion in mMC and differences in the localization of ß-catenin between the two groups. CONCLUSION: The patients' prognoses were significantly poorer depending on the histologic subtype (in the order pure A, pure B, and mixed). MUC1 localization and ß-catenin were revealed as independent predictors contributing to the poorer prognosis.

Utility of human epidermal growth factor 2 heterogeneity as a prognostic factor in triple-negative breast cancer.

In some cases of human epidermal growth factor 2 (HER2)-negative breast cancer, including triple-negative breast cancer, HER2 expression is sporadically and strongly upregulated, a condition known as HER2 heterogeneity. We investigated the clinicopathological features of patients with HER2 heterogeneity in triple-negative breast cancers treated with neoadjuvant chemotherapy. Thirty-nine patients with triple-negative breast cancer who had undergone preoperative chemotherapy participated in this study. To assess for HER2 heterogeneity, we used dual in situ hybridization slides. We evaluated the association between HER2 heterogeneity and clinicopathological factors such as rates of pathologic complete response (pCR) and of recurrence-free survival. Of the 39 patients, 15 (38.5%) had cancers with HER2 heterogeneity. The pCR rates were 13.3% among patients with HER2 heterogeneity and 20.8% among those with HER2 nonheterogeneity, but the difference was not significant. The recurrence-free survival rate was significantly lower in patients with HER2 heterogeneity than in those without (P = 0.025). HER2 heterogeneity is a significant predictor of poor prognosis in patients with triple-negative breast cancer treated with neoadjuvant chemotherapy.

Current status and prospects of artificial intelligence in breast cancer pathology: convolutional neural networks to prospective Vision Transformers.

Breast cancer is the most prevalent cancer among women, and its diagnosis requires the accurate identification and classification of histological features for effective patient management. Artificial intelligence, particularly through deep learning, represents the next frontier in cancer diagnosis and management. Notably, the use of convolutional neural networks and emerging Vision Transformers (ViT) has been reported to automate pathologists' tasks, including tumor detection and classification, in addition to improving the efficiency of pathology services. Deep learning applications have also been extended to the prediction of protein expression, molecular subtype, mutation status, therapeutic efficacy, and outcome prediction directly from hematoxylin and eosin-stained slides, bypassing the need for immunohistochemistry or genetic testing. This review explores the current status and prospects of deep learning in breast cancer diagnosis with a focus on whole-slide image analysis. Artificial intelligence applications are increasingly applied to many tasks in breast pathology ranging from disease diagnosis to outcome prediction, thus serving as valuable tools for assisting pathologists and supporting breast cancer management.

Cancer-associated fibroblast spatial heterogeneity and EMILIN1 expression in the tumor microenvironment modulate TGF-ß activity and CD8+ T-cell infiltration in breast cancer.

Rationale: The tumor microenvironment (TME) and its multifaceted interactions with cancer cells are major targets for cancer treatment. Single-cell technologies have brought major insights into the TME, but the resulting complexity often precludes conclusions on function. Methods: We combined single-cell RNA sequencing and spatial transcriptomic data to explore the relationship between different cancer-associated fibroblast (CAF) populations and immune cell exclusion in breast tumors. The significance of the findings was then evaluated in a cohort of tumors (N=75) from breast cancer patients using immunohistochemistry analysis. Results: Our data show for the first time the degree of spatial organization of different CAF populations in breast cancer. We found that IL-iCAFs, Detox-iCAFs, and IFNγ-iCAFs tended to cluster together, while Wound-myCAFs, TGFß-myCAFs, and ECM-myCAFs formed another group that overlapped with elevated TGF-ß signaling. Differential gene expression analysis of areas with CD8+ T-cell infiltration/exclusion within the TGF-ß signaling-rich zones identified elastin microfibrillar interface protein 1 (EMILIN1) as a top modulated gene. EMILIN1, a TGF-ß inhibitor, was upregulated in IFNγ-iCAFs directly modulating TGFß immunosuppressive function. Histological analysis of 75 breast cancer samples confirmed that high EMILIN1 expression in the tumor margins was related to high CD8+ T-cell infiltration, consistent with our spatial gene expression analysis. High EMILIN1 expression was also associated with better prognosis of patients with breast cancer, underscoring its functional significance for the recruitment of cytotoxic T cells into the tumor area. Conclusion: Our data show that correlating TGF-ß signaling to a CAF subpopulation is not enough because proteins with TGF-ß-modulating activity originating from other CAF subpopulations can alter its activity. Therefore, therapeutic targeting should remain focused on biological processes rather than on specific CAF subtypes.

Fibrocystic breast disease with pleomorphic calcifications and segmental distribution: A case report.

Fibrocystic breast disease is the most common benign condition and is important for differentiating breast cancer. We present the case of a 27-year-old female patient with pleomorphic calcifications and segmental distribution on mammography, which was highly suggestive of breast cancer; however, the pathological findings were fibrocystic disease. Although fibrocystic breast disease does not require treatment, appropriate follow-up is necessary after assessing the risk of breast cancer.

Identification of MicroRNAs Associated with Histological Grade in Early-Stage Invasive Breast Cancer.

This study aimed to identify microRNAs associated with histological grade using comprehensive microRNA analysis data obtained by next-generation sequencing from early-stage invasive breast cancer. RNA-seq data from normal breast and breast cancer samples were compared to identify candidate microRNAs with differential expression using bioinformatics. A total of 108 microRNAs were significantly differentially expressed in normal breast and breast cancer tissues. Using clinicopathological information and microRNA sequencing data of 430 patients with breast cancer from The Cancer Genome Atlas (TCGA), the differences in candidate microRNAs between low- and high-grade tumors were identified. Comparing the expression of the 108 microRNAs between low- and high-grade cases, 25 and 18 microRNAs were significantly upregulated and downregulated, respectively, in high-grade cases. Clustering analysis of the TCGA cohort using these 43 microRNAs identified two groups strongly predictive of histological grade. miR-3677 is a microRNA upregulated in high-grade breast cancer. The outcome analysis revealed that patients with high miR-3677 expression had significantly worse prognosis than those with low miR-3677 expression. This study shows that microRNAs are associated with histological grade in early-stage invasive breast cancer. These findings contribute to the elucidation of a new mechanism of breast cancer growth regulated by specific microRNAs.

A Randomized Controlled Phase 2 Study of Neoadjuvant Eribulin Versus Paclitaxel in Women with Operable Breast Cancer: The JONIE-3 Study.

OBJECTIVE: Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel. METHODS: In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis. RESULTS: One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E. CONCLUSION: Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.

Strontium-89 plus zoledronic acid versus zoledronic acid for patients with painful bone metastatic breast cancer.

INTRODUCTION: ß-ray strontium-89 (Sr-89) intra-irradiation therapy has been approved and clinically used to reduce bone metastasis pain not alleviated by bone-modifying agents, external radiation, and analgesic agents. We examined the efficacy of zoledronic acid (ZOL) and Sr-89 combination therapy compared with ZOL alone in breast cancer patients with bone metastases. MATERIALS AND METHODS: A randomized controlled trial was conducted on breast cancer patients with bone metastasis to compare the efficacy between ZOL monotherapy and ZOL plus Sr-89 combination therapy. The primary endpoints were changes in urinary NTX levels at 13 weeks and brief pain inventory scores. The secondary endpoints were analgesic drug usages, response rates, changes in bone metabolism markers, quality of life, and adverse event rates. RESULTS: Thirty of the planned 60 cases were randomly assigned to ZOL alone or ZOL + Sr-89. There were no significant differences in the changes in urinary NTX levels between the 2 groups (P = 0.365). There was no consistent difference in the pain score changes between the 2 groups. Sr-89 addition to ZOL slightly reduced the white blood cell and platelet counts. However, all adverse events were Grade 1. Safety and analgesic drug dose reduction were more evident in ZOL + Sr-89. CONCLUSION: This trial showed the lack of benefits from Sr-89 addition to ZOL for breast cancer patients with painful bone metastases. However, safety and analgesic drug dose reduction were more evident in ZOL + Sr-89, indicating its potential for pain control. Sr-89 therapy is safe, thus more effective radiopharmaceuticals are anticipated.

Association of L-type amino acid transporter 1 (LAT1) with the immune system and prognosis in invasive breast cancer.

L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16-7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35-8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer.

Prognostic value of tumor-infiltrating lymphocytes in estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

Tumor-infiltrating lymphocytes (TILs) are a significant prognostic factor in triple-negative breast cancer. However, the clinicopathological significance of TILs in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer remains unclear. The purpose of the present study was to evaluate the role of TILs in the prognosis of ER-positive and HER2-negative breast cancer. A total of 65 consecutive patients with ER-positive and HER2-negative breast cancer were examined. TILs in stromal tissue (str-TILs) were graded using the International TILs Working Group criteria. The association between several clinicopathological factors and TIL grade were investigated, and the prognostic impact of TILs was compared between luminal A-like and luminal B-like breast cancer. A total of 51 patients (78.5%) had low-grade (0-10%), 11 (16.9%) had intermediate (10-40%) and 3 (4.6%) had high-grade (40-90%) str-TIL levels. There was a significant association between high levels of Ki67 expression and a high str-TIL count. Relapse-free survival was significantly worse in patients with luminal B-like cancer compared with that in patients with luminal A-like cancer. Patients with an intermediate or high str-TIL count had a better prognosis compared with those with a low str-TIL count. All patients with luminal B-like cancer and intermediate or high str-TIL levels developed no recurrence during follow-up. In conclusion, there was a significant correlation between high-grade str-TIL levels and high tumor cell proliferation rate, as well as high levels of Ki67 expression.

Phase II study of sequential S-1 and cyclophosphamide therapy in patients with metastatic breast cancer.

BACKGROUND: S-1 and cyclophosphamide (CPA) can be given orally, and their combination may have great potential for treating metastatic breast cancer (MBC). A phase I study of sequential S-1 and CPA therapy was conducted in patients with MBC; the recommended doses that were determined for this regimen were 80 mg/m2/day for S-1 and 100 mg/m2/day for CPA. We then conducted a phase II study of this oral S-1 and CPA regimen. METHODS: This was a single-arm, open-label, single-center prospective phase II study to evaluate the efficacy of a sequential S-1 and CPA regimen for MBC. S-1 was administered orally 2×/day for 14 consecutive days, and then CPA was administered orally 2×/day for 14 consecutive days in a repeating 4-week cycle (S-1 for 2 weeks, CPA for 2 weeks). The primary endpoint was the overall response rate (ORR). Secondary endpoints included the overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety. RESULTS: Thirty-six patients were enrolled in this study. The overall response was complete response in 0 (0%), partial response in 12 (33.3%), stable disease in 12 (33.3%), and progressive disease in 11 (30.1%) patients. The ORR was 33.3% (12/36). The CBR was 66.7% (24/36). The median PFS was 9.5 months (95%CI: 7.8-12.6 months). The median OS was 20.2 months (95%CI: 15.0-25.4 months) Grade 3/4 adverse events included leukopenia in seven patients (19.4%). Dose reductions because of adverse events occurred in 12 patients (33.3%). There was no treatment-related mortality. CONCLUSION: The combination of sequential therapy with S-1 and CPA was tolerable and had efficacy with good disease control. Sequential therapy with S-1 and CPA may be a feasible new treatment option for patients with MBC; however, further study is warranted to explore the efficacy of this therapy. TRIAL REGISTRATION: JRCT, JRCTs031180296 . Registered 2 December 2019 - Retrospectively registered.

Implications of Topoisomerase (TOP1 and TOP2α) Expression in Patients With Breast Cancer.

BACKGROUND/AIM: We evaluated the usefulness of topoisomerases (TOPs) expression as prognostic predictors in breast cancer. PATIENTS AND METHODS: We retrospectively investigated sixty cases with primary breast cancer. We evaluated the tumor and non-tumor mRNA levels of TOP1 and TOP2α using quantitative reverse-transcription polymerase chain reaction. TOP1/TOP2α positivity was defined as the ratio of the mRNA expression of cancer/normal tissue of >1 for both TOP1 and TOP2α. RESULTS: TOP1 and TOP2α were markedly overexpressed in breast cancer tissues compared to normal breast tissues. Of the 60 cases, 46 (76.7%) were positive for TOP1/TOP2α. The relapse-free survival was relatively shorter for patients with positive TOP1/TOP2α. There was no recurrent disease among the 14 patients who were negative for TOP1/TOP2α, whereas four of the 46 TOP1/TOP2α-positive patients had disease recurrence. CONCLUSION: Negative TOP1 or TOP2α expression may be useful for predicting better prognoses in breast cancer patients.

The pathological complete response and secreted protein acidic and rich in cysteine expression in patients with breast cancer receiving neoadjuvant nab-paclitaxel chemotherapy.

Biomarkers that can accurately predict treatment response are required for indicating optimal neoadjuvant treatments. The current study assessed the predictive value of secreted protein acidic and rich in cysteine (SPARC) mRNA expression for the response to neoadjuvant nab-paclitaxel (nab-PTX) therapy in patients with breast cancer. It was hypothesized that SPARC expression can affect the response to albumin-bound taxanes, including nab-PTX since SPARC binds albumin with a high affinity. Pre-therapeutic specimens of core needle biopsies were analyzed from 50 patients in a phase II trial of neoadjuvant nab-PTX and the factors that were associated with a pathological complete response (pCR) were assessed. The pre-therapeutic tumor mRNA levels of chemotherapy-related proteins were quantified, including SPARC, and the correlations with post-therapeutic clinicopathological factors were assessed, including with pCR. The results demonstrated that pre-therapeutic SPARC mRNA expression was significantly higher in non-pCR patients compared with patients with pCR (92.37±55.33 vs. 56.53±30.19; P=0.027). A cutoff point of 48.5 was determined using receiver operating characteristic (ROC) curve analysis (sensitivity, 83.3%; specificity, 50.0%), and patients were classified into low and high SPARC expression groups. High SPARC expression was associated with histological grade (P=0.035), estrogen receptor expression (P=0.037), and progesterone receptor expression (P=0.002) but not with HER2 (P=0.895), and Ki-67 LI (P=0.743) expression. The results of the current study indicated that a high SPARC mRNA expression was a negative predictor of pCR following neoadjuvant nab-PTX therapy regardless of breast cancer subtype. The phase II study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the National Hospital Organization Takasaki General Medical Center (Registration nos. H23-9 and H23-33).

RNA-sequence-based microRNA expression signature in breast cancer: tumor-suppressive miR-101-5p regulates molecular pathogenesis.

Aberrantly expressed microRNA (miRNA) are known to disrupt intracellular RNA networks in cancer cells. Exploring miRNA-dependent molecular networks is a major challenge in cancer research. In this study, we performed RNA-sequencing of breast cancer (BrCa) clinical specimens to identify tumor-suppressive miRNA in BrCa. In total, 64 miRNA were identified as candidate tumor-suppressive miRNA in BrCa cells. Analysis of our BrCa signature revealed that several miRNA duplexes (guide strand/passenger strand) derived from pre-miRNA were downregulated in BrCa tissues (e.g. miR-99a-5p/-3p, miR-101-5p/-3p, miR-126-5p/-3p, miR-143-5p/-3p, and miR-144-5p/-3p). Among these miRNA, we focused on miR-101-5p, the passenger strand of pre-miR-101, and investigated its tumor-suppressive roles and oncogenic targets in BrCa cells. Low expression of miR-101-5p predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0316). Ectopic expression of miR-101-5p attenuated aggressive phenotypes, e.g. proliferation, migration, and invasion, in BrCa cells. Finally, we identified seven putative oncogenic genes (i.e. High Mobility Group Box 3, Epithelial splicing regulatory protein 1, GINS complex subunit 1 (GINS1), Tumor Protein D52, Serine/Arginine-Rich Splicing Factor Kinase 1, Vang-like protein 1, and Mago Homolog B) regulated by miR-101-5p in BrCa cells. The expression of these target genes was associated with the molecular pathogenesis of BrCa. Furthermore, we explored the oncogenic roles of GINS1, whose function had not been previously elucidated, in BrCa cells. Aberrant expression of GINS1 mRNA and protein was observed in BrCa clinical specimens, and high GINS1 expression significantly predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0126). Knockdown of GINS1 inhibited the malignant features of BrCa cells. Thus, identification of tumor-suppressive miRNA and molecular networks controlled by these miRNA in BrCa cells may be an effective strategy for elucidation of the molecular pathogenesis of this disease.

Clinicopathological values of PD-L1 expression in HER2-positive breast cancer.

Several ongoing clinical trials are investigating the use of immuno-targeting therapy with programmed cell death protein-1 and programmed death-ligand 1 (PD-L1) inhibitors for triple-negative breast cancer. However, the role of PD-L1 expression in HER2-positive breast cancer remains unclear. We investigated the clinicopathological utility of PD-L1 expression in HER2-positive breast cancer. Cohort A included 248 patients with invasive breast cancer (all subtypes). Cohort B included 126 HER2-positive patients who received neoadjuvant chemotherapy (NAC) concomitant with trastuzumab. The relationship of PD-L1 expression on the cancer cells with clinicopathological factors including pathological complete response (pCR) and prognosis was investigated. In cohort A, 8.1% patients were PD-L1-positive; PD-L1 positivity showed a correlation with high degree of tumor-infiltrating lymphocytes (TILs), estrogen receptor negativity, progesterone receptor negativity, and high histological grade. In cohort B, 17.5% patients were PD-L1-positive; PD-L1 positivity showed a significant correlation with high degree of TILs and high abundance of CD8-positive TILs. The pCR rates were related to TILs and PD-L1 expression. Among PD-L1-negative patients, high CD8-positive TILs were associated with significantly better prognosis. In conclusion, 17.5% of HER2-positive type patients were PD-L1-positive. PD-L1 expression was associated with response to NAC with trastuzumab in patients with HER2-positive breast cancer.

Risk Analysis for Chemotherapy-induced Nausea and Vomiting (CINV) in Patients Receiving FEC100 Treatment.

BACKGROUND/AIM: Risk factors for chemotherapy-induced nausea and vomiting (CINV) with anthracycline-containing regimen for breast cancer patients remain unknown. The risk factors for CINV with FEC100 were investigated. PATIENTS AND METHODS: Data on CINV events and patient backgrounds of 180 patients were collected from the first cycle of FEC100 treatment. In this regimen, patients were administered various antiemetics (ADs). The combinations of ADs were classified into four categories, while body mass index (BMI) was stratified into three categories. Risk factors were selected based on patient characteristics and combination of ADs. Risks for CINV were analyzed by univariate and multivariate analyses. RESULTS: In the univariate analysis of nausea, BMI was a significant factor, while BMI and combination of ADs were significant in vomiting. In the multivariate analysis concerning nausea, BMI was a significant factor. In the analysis concerning vomiting, the combination of ADs and BMI were significant. CONCLUSION: BMI was the most important risk factor for nausea and vomiting, while the combination of ADs was for vomiting.

ß2-Adrenergic receptor expression is associated with biomarkers of tumor immunity and predicts poor prognosis in estrogen receptor-negative breast cancer.

PURPOSE: Antitumor immunity plays an important role in the progression of breast cancer. ß2-adrenergic receptor (ß2AR) was found to regulate the antitumor immune response and breast cancer progression in preclinical studies. To understand the clinical role of ß2AR in cancer progression, we investigated the clinicopathological and prognostic significance of ß2AR expression in invasive breast cancer. METHODS: ß2AR levels in breast tumors were evaluated by immunohistochemistry in a well-characterized patient cohort with long-term follow-up (n = 278). We evaluated the relationship of ß2AR expression to patient survival and clinicopathological factors, including immune biomarkers such as tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. Breast cancer-specific survival was compared between high- and low-ß2AR expression groups. RESULTS: Although ß2AR was not related to clinicopathological factors across the whole cohort, high ß2AR was significantly related to PD-L1 negativity in estrogen receptor (ER)-negative patients. Tumors with high ß2AR tended to have low TIL grade, and high ß2AR was an independent prognostic factor for reduced survival in ER-negative patients. CONCLUSIONS: ß2AR is an independent poor prognostic factor in ER-negative breast cancer. The findings suggest that tumor ß2AR regulates immune checkpoint activity, which may have therapeutic implications for patients with ER-negative breast cancer.

Utility of Ki67 labeling index, cyclin D1 expression, and ER-activity level in postmenopausal ER-positive and HER2-negative breast cancer with neoadjuvant chemo-endocrine therapy.

In this study, we investigated the relationships of pathological response after neoadjuvant chemo-endocrine therapy with alterations in the Ki67 labeling index (LI), expression of cyclin D1 (CCND1) and progesterone receptor (PgR), and estrogen receptor (ER) activity in breast cancer. A total of 43 Japanese post-menopausal ER-positive and human epidermal growth factor receptor 2-negative invasive breast cancer patients with tumors >2 cm or positive lymph nodes were enrolled. Exemestane alone was administered for 2 months. Neoadjuvant chemo-endocrine therapy included four cycles of doxorubicin plus paclitaxel followed by weekly paclitaxel. The immunohistochemical expression of Ki67 LI, CCND1, and PgR, and ER activity were evaluated using core needle biopsy samples at the pretreatment and post-exemestane alone stages. ER activity was evaluated through transfection of an adenovirus vector carrying an estrogen-response element-green fluorescent protein gene. In current study, marked pathological responses (including 4.7% with pathological complete response) were obtained in 34.9% of patients. Ki67 LI and PgR expression were significantly decreased after treatment. High Ki67 LI at pretreatment was a significant predictive factor of marked pathological response. At the stage of post-exemestane alone, Ki67 LI was not significantly associated with pathological response; however, high CCND1 expression was significantly correlated with high Ki67 LI. Moreover, low-level ER activity at the post-exemestane alone stage was significantly associated with marked pathological response. In conclusions, pretreatment Ki67 LI was a predictor of response to neoadjuvant chemo-endocrine therapy. CCND1 expression and ER activity at the post-endocrine therapy alone stage may be useful in determining further treatments.

Prognostic significance of tumour-infiltrating lymphocytes for oestrogen receptor-negative breast cancer without lymph node metastasis.

Tumour-infiltrating lymphocytes (TILs) are regarded as significant prognostic markers in patients with breast cancer. However, the prognostic utility of TIL expression based on the intrinsic subtypes has just been identified. The present study investigated the relationship between TIL grades and prognosis in 294 Japanese paitents with breast cancer stratified based on the intrinsic subtypes and clinicopathological characteristics. Stromal TIL status was evaluated using haematoxylin and eosin staining, and TIL grades were categorised into low (<10%), intermediate (≥10 and ≤40%) and high (>40%) groups. The relationship between TIL expression and the intrinsic subtypes, clinicopathological characteristics and patient prognosis was analyzed. It was revealed that high TIL expression was correlated with negative oestrogen receptor (ER) expression and high histological grade (P<0.001). Among the ER-negative patients, the relapse-free survival (RFS) rate of the high-grade TIL group was significantly higher than that of the low-grade TIL group (P=0.04). Among the ER-negative patients without lymph node metastasis, RFS and cancer-specific survival (CSS) rates of patients with high-grade TILs were significantly higher than the RFS and CSS rates of patients with low-grade TILs (P=0.01). However, among ER-positive patients, RFS was significantly higher in the low-grade TIL group than in the high-grade TIL group (P=0.02). In conclusion, TIL expression correlated with ER status and tumour proliferation. High TIL expression was a poor prognostic marker in ER-positive patients but was a good prognostic marker in ER-negative patients. Therefore, the biological association between TILs and primary breast tumours may differ between ER-positive and ER-negative breast cancer.