Efficacy of the eribulin, pertuzumab, and trastuzumab combination therapy for human epidermal growth factor receptor 2-positive advanced or metastatic breast cancer: a multicenter, single arm, phase II study (JBCRG-M03 study).

Purpose To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast cancer (AMBC), this multicenter, open-label, phase II trial (JBCRG-M03: UMIN000012232) presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab. Methods We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013-April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and trastuzumabplus pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety. Results Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients [95% confidence interval (CI): 7.0-11.4]. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed. Conclusions In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC. Trial registration ID: UMIN-CTR: UMIN000012232.

Advantage of sentinel lymph node biopsy before neoadjuvant chemotherapy in breast cancer treatment.

Lymph node status is a key factor in determining the stage of breast cancer and the most appropriate therapy and for predicting the outcome of patients. Accurate identification of sentinel lymph nodes (SLNs) preoperatively is of clinical importance. Sentinel lymph node biopsy (SLNB) causes less lymph edema of the upper arm than axillary lymph node dissection (ALND) with a high accuracy rate and low false-negative rate (FNR). Neoadjuvant chemotherapy (NAC) can be given not only to patients with locally advanced breast cancer, but also to those with axillary lymph node metastasis and an operable tumor. However, SLNB after NAC results in a lower identification rate and a higher FNR than SLNB before treatment. Recently, a hybrid imaging device has been developed, which consists of single photon emission computed tomography (CT, SPECT) and a low-dose CT installed on the same platform. This imaging system offers an easy and safe method of performing SLNB under local anesthesia. To identify the initial cancer stage in patients who will be treated by systemic therapy before surgery, SLNB should be performed prior to systemic treatments, using a well-developed navigating tool, such as SPECT/CT.

[A case of spindle cell carcinoma of the breast including metaplastic lesion with poor prognosis].

A 57-year-old woman complained of a huge and rapid growing mass with bleeding in the left breast. Breast imaging (CT and MRI)showed a large, irregular and unevenly enhanced tumor with lymph node swelling in the left axilla. Mastectomy and axillary lymph node dissection were performed for control of bleeding from the tumor in the left breast. Pathological diagnosis was spindle cell carcinoma of the breast with transition from papillotubular carcinoma. Although the patient was treated with adjuvant chemotherapy and trastuzumab according to the treatment guideline for conventional breast cancer, she had an early relapse with mediastinal metastasis and died 9 months after operation. The tumor showed metaplastic change from epithelial tumor to spindle cell carcinoma. Because the epithelial part expressed weakly positive estrogen receptor(ER), progesterone receptor(PgR)-negative and HER2-positive, we used trastuzumab for adjuvant therapy. However, part of the spindle cell tumor mainly showed triple-negative, and ER, PgR and HER2 expression were negative, which might explain her poor prognosis for resistance to trastuzumab.

Identification of biomarkers in ductal carcinoma in situ of the breast with microinvasion.

BACKGROUND: Widespread use of mammography in breast cancer screening has led to the identification of increasing numbers of patients with ductal carcinoma in situ (DCIS). DCIS of the breast with an area of focal invasion 1 mm or less in diameter is defined as DCIS with microinvasion, DCIS-Mi. Identification of biological differences between DCIS and DCIS-Mi may aid in understanding of the nature and causes of the progression of DCIS to invasiveness. METHODS: In this study, using resected breast cancer tissues, we compared pure DCIS (52 cases) and DCIS-Mi (28 cases) with regard to pathological findings of intraductal lesions, biological factors, apoptosis-related protein expression, and proliferative capacity through the use of immunohistochemistry and the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method. RESULTS: There were no differences in biological factors between DCIS and DCIS-Mi, with respect to levels of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2. The frequency of necrosis and positive expression ratio of survivin and Bax were significantly higher in DCIS-Mi than in DCIS. In addition, apoptotic index, Ki-67 index, and positive Bcl-2 immunolabeling tended to be higher in DCIS-Mi than in DCIS. Multivariate analysis revealed that the presence of necrosis and positive survivin expression were independent factors associated with invasion. CONCLUSION: Compared with DCIS, DCIS-Mi is characterized by a slightly elevated cell proliferation capacity and enhanced apoptosis within the intraductal lesion, both of which are thought to promote the formation of cell necrotic foci. Furthermore, the differential expression of survivin may serve in deciding the response to therapy and may have some prognostic significance.

Reduced expression of the breast cancer metastasis suppressor 1 mRNA is correlated with poor progress in breast cancer.

PURPOSE: It is well established that breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis of breast cancer in animal models without affecting the growth of the primary tumor. It has also been shown to suppress the metastasis of tumors derived from breast and melanoma cell lines. However, its clinical importance for breast cancer patients remains undetermined. This prompted us to investigate its expression level in breast cancer patients to clarify its clinical significance. EXPERIMENTAL DESIGN: The level of expression of BRMS1 mRNA was assessed by LightCycler quantitative real-time reverse transcription-PCR in 161 cases of invasive carcinoma of the breast. Associations between BRMS1 mRNA expression and various clinicopathologic factors were sought. RESULTS: It was found that BRMS1 mRNA was expressed at significantly higher levels in patients>50 years of age, with tumor size<2 cm, or with progesterone receptor-positive and HER2-negative tumors. No differences were found between BRMS1 mRNA expression and axillary lymph node metastasis and histologic grade groups. Patients with high levels of expression of BRMS1 mRNA have a better prognosis than those with low expression. Univariate and multivariate prognostic analysis showed that BRMS1 mRNA is an independent prognostic factor for disease-free survival in breast cancer. CONCLUSIONS: These results provide clinical evidence to support the notion that BRMS1 is a breast carcinoma metastasis suppressor gene. Our results also suggest that measuring BRMS1 expression will help to identify those breast cancer patients with worse disease-free survival.

A case report of paraneoplastic neurological syndrome associated with occult breast cancer.

Paraneoplastic syndromes are the rarest neurological complications in patients with breast cancer. Here, we present a case of occult breast cancer presenting as paraneoplastic sensory neuropathy. A 47-year-old woman developed progressive upper and lower extremity weaknesses with paresthesia and gait ataxia. Multiple cerebrospinal fluid (CSF) analyses and magnetic resonance image (MRI) scans of her brain and spine offered no diagnosis. Although no paraneoplastic antibodies were found, paraneoplastic neurological syndrome was suspected after examination by the neurologist eliminated other possibilities. Her mammogram demonstrated pleomorphic calcifications. Although local and systemic therapies were given, no significant improvement in the neurologic condition was found.

Associations Between Elastography Findings and Clinicopathological Factors in Breast Cancer.

This study aimed to explore the clinical significance of breast tumor tissue stiffness based on ultrasound elastographic evaluation in clinical breast cancer. Tumor tissue stiffness is mainly regulated by interactions among tumor cells, stromal cells, and extracellular matrix and was recently regarded as a representative feature of tumor microenvironment. Basic research has already revealed that the tumor stiffness can lead to tumor progression; however, little is known about its clinical significance because thus far, no useful modality is available in the clinical setting. We investigated the tumor stiffness by strain elastography in 503 consecutive patients with invasive breast cancer. Correlations between stiffness and clinicopathological factors, including tumor size, lymph node involvement, tumor subtypes, and stromal-related genes' expressions in primary breast tumor, were statistically examined. We identified that clinical tumor stiffness significantly correlated with lymph node involvement and invasive tumor size but not with hormonal receptor expressions, human epidermal growth factor receptor type 2 status, and ki67 labeling index by analyses of both categorical and continuous variables of stiffness. On multivariate analyses, axillary lymph node metastasis was an independent factor that influenced the stiffness of primary breast tumor. In the gene expression analyses, relatively hard tumors had a significantly high gene expression of lysyl oxidase compared with soft tumors. Our study showed a close relationship between primary tumor stiffness by elastographic evaluation and lymph node involvement in clinical breast cancer. Further investigations on tumor-related tissue stiffness are required.

Potential advantage of preoperative three-dimensional mapping of sentinel nodes in breast cancer by a hybrid single photon emission CT (SPECT)/CT system.

OBJECTIVE: This study aims to assess the role of three-dimensional single-photon emission computed tomography (3D-SPECT/CT) in sentinel node (SN) identification, and to analyze the impact of such information on estimating metastases to SNs. BACKGROUND: Nodal status is a key factor for breast cancer. SN biopsy has been established as the alternative to routine axillary dissection these days. We investigated both the anatomical location of SNs demonstrated by our 3D-SPECT/CT system and the correlation to SN positivity. METHODS: Two hundred and twenty-three clinically node-negative patients underwent SN biopsy. All of the axillary structures, including SNs, were visualized by a SPECT/CT combined system after subcutaneous injection of (99m)Tc-phytate. By plotting the visualized SNs, the most frequent SN location 'Pedestal area (PA)' was designated. RESULTS: SPECT/CT detected (99m)Tc uptake in 217 cases (97.3%). 3D-SPECT/CT images visualized the accurate location of SNs in each case. In patients whose SNs were histopathologically negative (SN-), 228 (98.3%) SNs were found in the PA, and 4 (1.7%) were in other zones. In those with histopathologically positive SNs (SN+), 65 (78.3%) SNs were in the PA and 18 (21.7%) were outside it. The difference in SN distribution (i.e., in or out of the PA) between SN+ and SN- patients was statistically significant (p<0.001, chi-square test). CONCLUSIONS: SN biopsy navigated by 3D-SPECT/CT can clarify the preoperative anatomical localization of SNs in patients with breast cancer. Atypical distribution of SNs out of the PA may suggest SN positivity, reflecting failure of the lymphatic drainage systems.

Clinical significance of basal-like subtype in triple-negative breast cancer.

BACKGROUND: No clinically useful target molecule has been identified for triple-negative (TN) breast cancer, i.e., estrogen receptor (ER)-negative, progesterone receptor (PgR)-negative, human epidermal growth factor receptor-2 (HER2)-negative phenotype, and its prognosis is poor. Triple-negative cancer consists of two subtypes: basal-like and non-basal-like. The aim of this study is to clarify the clinical and biological characteristics of these two subtypes of TN cancer. METHODS: We examined, by immunohistochemistry, expression of biological markers cytokeratin (CK) 5/6 and epidermal growth factor receptor (EGFR) in triple-negative breast cancer. Basal-like subtype was defined as CK5/6-positive and/or EGFR-positive, and non-basal-like subtype was defined as no expression of these two markers. We studied the correlation between basal-like subtype and several factors related to tumor progression, along with the prognostic value of basal-like subtype and other biological markers in triple-negative cancer. RESULTS: In the 48 cases of operable triple-negative breast cancer, basal-like subtype was detected in 22 (45.8%) and non-basal-like subtype in 26 (54.2%). Basal-like subtype was significantly correlated with nodal status (P = 0.0475) and nuclear grade (P = 0.0475). Basal-like subtype was also significantly associated with Ki67 labeling index (P = 0.0118), c-kit expression (P = 0.0335), and aurora A expression (P = 0.0020). No association was detected between basal-like cancer and other biological markers. Patients with basal-like subtype of triple-negative cancer showed shorter disease-free survival (P = 0.0049) and overall survival (P = 0.0283) than patients with non-basal-like subtype. No independent prognostic factors were identified among the prognostic factors obtained from univariate analysis. CONCLUSIONS: These findings suggest that basal markers can be used to classify triple-negative breast cancer into at least two subtypes with differing prognoses. It is necessary to develop a novel treatment strategy to improve the prognosis of patients with basal-like subtype of triple-negative breast cancer.

Nuclear corepressor 1 expression predicts response to first-line endocrine therapy for breast cancer patients on relapse.

BACKGROUND: Estrogen receptor alpha (ER alpha) is the most important endocrine therapy responsiveness predictor for women with breast cancer. The accuracy of the prediction of the response to endocrine therapy was thought to be affected by involving the estrogen receptor coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. Nuclear corepressor 1 (NCOR1) is one of the ER a transcription repressor. The objective of the study is to investigate the expression of NCOR1 at the protein level and pursue its predictive value for breast cancer endocrine therapy. METHODS: In the present study, the level of expression of NCOR1 protein has been assessed by immunohistochemistry in 104 cases of invasive carcinoma of the breast. Associations between NCOR1 protein expression and different clinicopathological factors and survival were sought. RESULTS: It was found that NCOR1 was expressed at significantly higher levels in responsive patients treated with endocrine therapy as first-line treatment on relapse. Responsive patients also had a significantly longer post-relapse survival and overall survival. No NCOR1 expression difference was found between patient by age, tumor size, lymph node status, different histological grade groups and human epidermal growth factor receptor 2 (HER2) status. Multivariate analysis showed that NCOR1 is an independent prognostic factor for over-all survival. CONCLUSIONS: In breast cancer, NCOR1 protein expression level predicts response to endocrine therapy as first-line treatment for breast cancer patients on relapse and NCOR1 protein level assay may increase the accuracy in the endocrine treatment determination and, therefore, improving the patients survival.

Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer.

PURPOSE: The aim of this study is to clarify characteristics of invasive breast cancer with expression of Hypoxia-induced factor 1alpha (HIF-1alpha) which is induced by hypoxia and signal transduction of growth factors. EXPERIMENTAL DESIGN: We examined, by immunohistochemical analysis, the expression of HIF-1alpha in normal breast tissue, benign disorders and breast cancer. In invasive breast cancer, we investigated the correlation between expression of HIF-1alpha and clinicopathological and biological factors. We also studied the prognostic value of HIF-1alpha in breast cancer. RESULTS: HIF-1alpha was mainly detected in tumor cell nuclei. In the 171 cases of invasive breast cancer examined, nuclear HIF-1alpha expression was detected in 63 (36.8%) cases. Immunoreactive nuclear HIF-1alpha was correlated with tumor size (p = 0.0013), lymph node metastasis (p = 0.0005), tumor stage (p = 0.0031) and histological grade (p = 0.0074). Elevated HIF-1alpha levels was also associated with hormone receptor negativity (p = 0.0025), HER2 overexpression (p = 0.0053), high Ki67 labeling index (p = 0.0002), increased levels of VEGF (p < 0.0001), COX-2 overexpression (p = 0.0029) and increased nuclear p53 (p = 0.0048). In terms of the possible use of HIF-1alpha as a prognostic indicator, patients who had increased HIF-1alpha levels in their tumor showed shorter disease-free survival (DFS) (p < 0.0001) and overall survival (OS) (p = 0.0002) than those lacking HIF-1alpha in univariate analysis. In multivariate analysis of DFS and OS, HIF-1alpha was identified an independent prognostic factor. CONCLUSIONS: These findings suggest that HIF-1alpha was closely linked to an aggressive phenotype in breast cancer. It may be useful to study the expression of HIF-1alpha using immunohistochemical analysis for better understanding of the tumor characteristics of breast cancer.