[Successful Treatment of Estrogen Receptor Positive, HER2 Negative Breast Cancer with Life-Threatening Multiple Bone Metastases Using the Combination of Fulvestrant and Palbociclib-A Case Report].

Palbociclib, a CDK4/6 inhibitor, is found to be an effective therapeutic drug in the treatment of estrogen receptor positive (ER+)metastatic breast cancer. In this report, we describe a case of rapid progression of life-threatening multiple bone metastases of breast cancer treated with a combination of fulvestrant and palbociclib. The patient, a 58-year-old postmenopausal woman, was diagnosed with left breast cancer at the age of 43 years and underwent breast-conserving surgery. After the completion of postoperative adjuvant endocrine therapy and radiotherapy, the patient was placed on regular follow-up. Eleven years after the surgery, multiple bone metastases and multiple lymph node metastases occurred, and the patient was treated with letrozole as first-line therapy for recurrent breast cancer. Although she continued to receive this treatment for 2 years and 10 months, her general condition worsened due to the occurrence of new liver metastases and the rapid progression of existing metastatic lesions. Thus, she was sent to an emergency room. Marked hypercalcemia and a severe decrease in erythrocyte and platelet counts were observed, which could be the cause of her worsening general condition. Her performance status(PS)was 4, and palliative treatment was also considered. However, she received treatment for hypercalcemia and red blood cell transfusion; as a result, she recovered to the PS 2 where she could begin chemotherapy. Then, she began a treatment consisting of a combination of fulvestrant and palbociclib as a second-line treatment for the recurrence. The patient responded well to the treatment, and her general condition improved to PS 1. She has since maintained a good quality of life for 2 years and 11 months without serious adverse events. In conclusion, the combination of fulvestrant and palbociclib has a low risk of serious adverse events and is a worthwhile treatment for rapidly progressing, life-threatening multiple bone metastases of breast cancer.

[A Case of Breast Mucinous Carcinoma with Bladder Metastasis Effectively Treated with Endocrine Therapy and Chemotherapy].

A 57-year-old Japanese woman underwent partial mastectomy of the right breast and sentinel lymph node biopsy in July 2005. The diagnosis was mucinous carcinoma with negative margins and no lymph node metastases(pT1cN0M0, pStage Ⅰ A). Postoperative adjuvant therapy included radiation therapy and oral administration of anastrozole for 5 years. In December 2015, we observed enlargement of left supraclavicular lymph nodes; a needle biopsy revealed lymph node metastases from breast cancer. We administered toremifene and the swelling disappeared. The patient was subsequently referred to the hospital for urinary frequency in November 2016. Imaging demonstrated a bladder tumor. Transurethral biopsy of bladder revealed adenocarcinoma with mucin production consistent with breast primary. After systemic chemotherapy(UFT, eribulin), endocrine therapy(fulvestrant), and molecular targeted therapy(palbociclib), her urologic symptoms were relieved. However, 2 years and 8 months after diagnosis of bladder metastasis, the patient showed disease progression and decided to discontinue all chemotherapy and pursue palliative care. We also present a review and discussion of the relevant literature.

Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy: a retrospective study and systematic review.

BACKGROUND: While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy. METHODS: To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions. RESULTS: The study population consisted of 277 patients who had received a median of 10 doses (range, 1-79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77-4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF. CONCLUSIONS: We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

Neoadjuvant chemotherapy with trastuzumab, docetaxel, and carboplatin administered every 3 weeks for Japanese women with HER2-positive primary breast cancer: efficacy and safety.

BACKGROUND: This phase II neoadjuvant study evaluated the efficacy and safety of a triweekly regimen of docetaxel and carboplatin in combination with trastuzumab (TCbH) in Japanese women with human epidermal growth factor receptor type2 (HER2)-positive primary breast cancer. METHODS: Patients with HER2-positive, stage I-III invasive breast cancer received six courses of trastuzumab (8 mg/kg loading dose, then 6 mg/kg, day 1), docetaxel (75 mg/m2, day 1), and carboplatin (area under the curve: 6, day 1) every 3 weeks. The primary endpoint was pathological complete response (pCR) of both breast and axillary lymph node disease. RESULTS: Fifty patients were enrolled in this study. Median age was 58 (range 32-75) years. All patients underwent definitive surgery. Thirty-three (66%) patients completed the chemotherapy course, while the treatment was delayed or discontinued in the other 17 (34%) patients because of adverse events (AEs). The pCR rate was 52%; the overall response rate was 66%. Grade 3/4 AEs due to nonhematological toxicity were anorexia (4%), diarrhea (2%), and rash (2%), and those due to hematological toxicity were neutropenia (36%), anemia (12%), and thrombocytopenia (2%). CONCLUSION: Although the triweekly six-course regimen of TCbH achieved a high pCR rate, hematological AEs frequently occurred during the latter part of the chemotherapy course. One-third of patients experienced delayed or discontinued chemotherapy. Clinical registration number: http://www.umin.org.au UMIN000013513.

Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.

Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti-HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. In this open-label, multicenter, dose-escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose-limiting toxicities and other non-life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression-free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose-limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression-free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI-121772.).

In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab.

BACKGROUND: Eribulin mesylate (eribulin) is a first-in-class halichondrin B-based microtubule dynamics inhibitor. To compare the anti-angiogenic activity of eribulin to that of bevacizumab, we compared tumour vessel remodelling and reoxygenation between the two agents. METHODS: Patients with advanced breast cancer with stage III/IV were eligible for the study. Patients were assigned to receive either eribulin or single-agent bevacizumab. Tissue concentrations of oxyhaemoglobin (O2Hb) and deoxyhaemoglobin (HHb), and oxygen saturation (SO2) of breast tumours before and day 7 after the first infusion were repeatedly measured using diffuse optical spectroscopic imaging (DOSI). A pair of blood samples was collected for multiplex biomarker studies. RESULTS: Baseline DOSI measurement of all 29 patients (eribulin, n=14 and bevacizumab, n=15) revealed significantly higher tumour concentrations of O2Hb and HHb than that in the normal breast tissue. After eribulin treatment, DOSI revealed a significant decrease in HHb concentration and increased SO2 during the observation period. This trend was not observed for bevacizumab. Instead, bevacizumab significantly decreased the concentration of O2Hb. The multiplex biomarker study revealed that both eribulin and bevacizumab decreased plasma concentrations of VEGF and bFGF, but only eribulin treatment suppressed the plasma concentration of TGF-ß1. CONCLUSIONS: Eribulin, but not bevacizumab, treatment increased tumour SO2. Suppression of TGF-ß1 by eribulin could have a favourable anti-angiogenic effect. Our results suggest that differences in vascular remodelling between these two agents may account for their different effects on tumour reoxygenation.

Near-Infrared Diffuse Optical Imaging for Early Prediction of Breast Cancer Response to Neoadjuvant Chemotherapy: A Comparative Study Using 18F-FDG PET/CT.

UNLABELLED: Diffuse optical spectroscopic imaging (DOSI) is used as an indicator of tumor blood volume quantified by tissue hemoglobin concentrations. We aimed to determine whether early changes in tumor total hemoglobin (tHb) concentration can predict a pathologic complete response (pCR) to neoadjuvant chemotherapy in patients with operable breast cancer, and we compared the predictive value of pCR between DOSI and (18)F-FDG PET combined with CT. METHODS: Of the 100 patients enrolled, 84 patients were prospectively evaluated for primary objective analysis. Sixty-four of the patients underwent both sequential DOSI scans at baseline after their first and second chemotherapy courses and (18)F-FDG PET/CT at baseline and after their second chemotherapy course. The mean tHb (tHbmean) concentration and SUVmax of the lesion were measured using DOSI and (18)F-FDG PET/CT, respectively, and the percentage change in tHbmean (∆tHbmean) and change in SUVmax (∆SUVmax) were calculated. We compared the diagnostic performances of DOSI and (18)F-FDG PET/CT for predicting pCR via the analysis of the receiver-operating-characteristic curves. RESULTS: pCR was achieved in 16 patients, and neoadjuvant chemotherapy caused a significant reduction of ∆tHbmean in pCR compared with non-pCR after the 2 chemotherapy courses. When the tentative ∆tHbmean cutoff values after the first and second courses were used, the ability to predict pCR was as follows: 81.2% sensitivity/47.0% specificity and 93.7% sensitivity/47.7% specificity, respectively. Comparison of the diagnostic performances of DOSI and (18)F-FDG PET/CT revealed areas under the curve of 0.69 and 0.75 of ∆tHbmean after the first and second courses, respectively, which were lower than those of ∆SUVmax (0.90). CONCLUSION: DOSI predicted pCR in patients with breast cancer with moderate accuracy. The diagnostic performance of DOSI was inferior to that of the early metabolic response as monitored by (18)F-FDG PET/CT.

Long-term combination chemotherapy using eribulin and trastuzumab for three patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

The combination chemotherapy regimen of eribulin (ERI) and trastuzumab (TRA)-the ERI-TRA regimen-has been shown to be highly tolerable for patients with recurrent or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no sufficient clinical evidence is available for the long-term safety profile of the regimen. We report on three patients in the Phase I combination study of the regimen, for whom the regimen could be conducted over the long term. Patient #1 was a 68-year-old woman and underwent the regimen until cycle 23. Patient #2 was a 61-year-old woman and underwent the regimen until cycle 27. Patient #3 was a 59-year-old woman and underwent the regimen until cycle 22. All these patients had undergone TRA-based combination therapy before the onset of the regimen. Any new categories of adverse events did not occur in association with the long-term combination chemotherapy. Neutropenia experienced by these patients was reversible and easily manageable by dose adjustment (interruption/delay and reduction). Neither increase in the risk of cardiomyopathy nor the worsening of peripheral neuropathy greater than grade 1 was found. The present regimen was suggested to be a novel chemotherapeutic option for patients with HER2-positive recurrent or metastatic breast cancer. The fact that the long-term ERI-TRA regimen was successfully conducted for these patients can be supplementary clinical information that is beneficial for clinical oncologists.

miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A.

Breast cancer is a hormone-dependent cancer and usually treated with endocrine therapy using aromatase inhibitors or anti-estrogens such as tamoxifen. A majority of breast cancer, however, will often fail to respond to endocrine therapy. In the present study, we explored miRNAs associated with endocrine therapy resistance in breast cancer. High-throughput miRNA sequencing was performed using RNAs prepared from breast cancer MCF-7 cells and their derivative clones as endocrine therapy resistant cell models, including tamoxifen-resistant (TamR) and long-term estrogen-deprived (LTED) MCF-7 cells. Notably, miR-21 was the most abundantly expressed miRNA in MCF-7 cells and overexpressed in TamR and LTED cells. We found that miR-378a-3p expression was downregulated in TamR and LTED cells as well as in clinical breast cancer tissues. Additionally, lower expression levels of miR-378a-3p were associated with poor prognosis for tamoxifen-treated patients with breast cancer. GOLT1A was selected as one of the miR-378a-3p candidate target genes by in silico analysis. GOLT1A was overexpressed in breast cancer specimens and GOLT1A-specific siRNAs inhibited the growth of TamR cells. Low GOLT1A levels were correlated with better survival in patients with breast cancer. These results suggest that miR-378a-3p-dependent GOLT1A expression contributes to the mechanisms underlying breast cancer endocrine resistance.

Neoadjuvant triweekly nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide for Stage II/III HER2-negative breast cancer: evaluation of efficacy and safety.

OBJECTIVE: Nanoparticle albumin-bound paclitaxel (nab-PTX) is a solvent-free paclitaxel coupled to human albumin without an associated increase in toxicity. The neoadjuvant study of primary breast cancer was planned to evaluate tumor response and safety of triweekly nanoparticle albumin-bound paclitaxel. METHODS: Patients with Stage II/III HER2-negative primary breast cancer received four courses of nanoparticle albumin-bound paclitaxel 260 mg/m(2) every 3 weeks (q3w), followed by four courses of epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) q3w. Tumor response after nanoparticle albumin-bound paclitaxel was histologically evaluated. In addition, the clinical response, breast-conserving rate and safety of this treatment were monitored. RESULTS: Among 53 patients who received nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide neoadjuvant chemotherapy, pathological complete response and near-pathological complete response were confirmed in 3 (5.7%) and 7 (13.2%) patients who had surgery, respectively. The overall objective response rate was 71.7% after completion of chemotherapy. Based on Positron Emission Tomography Response Criteria in Solid Tumors using (18)F-fluorodeoxyglucose, complete metabolic response and partial metabolic response after 2-3 courses of nanoparticle albumin-bound paclitaxel were 15.1 and 52.8%, respectively. The most common significant toxicities of q3w nanoparticle albumin-bound paclitaxel were Grade 3 muscle pain, neuropathy and febrile neutropenia, each in 1 (1.9%) patient. There were no incidences of anaphylaxis or Grade 4/5 adverse events. CONCLUSION: Neoadjuvant chemotherapy using q3w nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide was feasible in breast cancer patients with acceptable clinical response and drug tolerance, but conferred a low rate of pathological complete response. Monotherapy with q3w nanoparticle albumin-bound paclitaxel could be an appropriate substitute for solvent-based taxane in terms of therapeutic and safety management.

[Progress in second-line therapies for metastatic breast cancer].

It may be difficult to achieve complete cure for most metastatic breast cancer patients;thus, prolongation of overall survival and maintenance of the quality of life are often the main focus of treatment. In the treatment of metastatic breast cancer patients, it is important to choose the most appropriate therapeutic strategy based on substantial evidence that considers the biology of the tumor, including estrogen receptor(ER), progesterone receptor(PgR), and human epidermal growth factor receptor 2(HER2)status;the site and extent of the metastatic focus;the time to recurrence;prior treatment regimens;age; menopausal status;performance status;and the preference of the patient. A clinical subtype classification that is based on the tumor biology is typically utilized for devising a treatment strategy specific to each subtype. Expressly, first-line treatment options may include hormone therapy for hormone-positive breast cancers, antiHER2 therapy for HER2-positive breast cancers, and chemotherapy for hormone-negative and HER2-negative(triple negative)breast cancers. In recent years, with the development of regimens that are effective for every subtype, the treatments for breast cancer have undergone significant changes. In this section, we introduce the progress in the treatment for metastatic breast cancer, focusing specifically on second-line therapies according to each subtype.

Grading system for blood vessel tumor emboli of invasive ductal carcinoma of the breast.

We previously reported that the number of mitotic and apoptotic figures in tumor cells in blood vessel tumor emboli had the greatest significant power for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. The purpose of the present study was to devise a grading system for blood vessel tumor emboli based on the mitotic and apoptotic figures of tumor cells in blood vessel tumor emboli, enabling accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 263 invasive ductal carcinomas into the following 3 grades according to the numbers of mitotic and apoptotic figures in tumor cells located in blood vessels within 1 high-power field: grade 0, no blood vessel invasion; grade 1, absence of mitotic figures and presence of any number of apoptotic figures, or 1 mitotic figure and 0 to 2 apoptotic figures; and grade 2, 1 mitotic figure and 3 or more apoptotic figures, or 2 or more mitotic figures and 1 or more apoptotic figures. Multivariate analyses with well-known prognostic factors demonstrated that grade 2 blood vessel tumor emboli significantly increased the hazard ratios for tumor recurrence independent of the nodal status, pathological TNM stage, hormone receptor status, or HER2 status. The presently reported grading system for blood vessel tumor emboli is the strongest histologic factor for accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast.

Safety and feasibility of adjuvant chemotherapy with S-1 in Japanese breast cancer patients after primary systemic chemotherapy: a feasibility study.

BACKGROUND: Advanced breast cancer patients have a higher risk of postoperative recurrence than early-stage breast cancer patients. Recurrence is believed to be caused by the increase in micrometases, which were not eradicated by preoperative or postoperative chemotherapy. Therefore, a new therapeutic strategy that can improve treatment efficacy is mandatory for advanced breast cancer. S-1 was shown to be effective and safe in Japanese metastatic breast cancer patients treated with previous chemotherapy, including anthracyclines. Thus, in this study, we evaluated S-1 as adjuvant chemotherapy in breast cancer patients after standard primary systemic chemotherapy. METHODS: The treatment consisted of 18 courses (a 2-week administration and a 1-week withdrawal; one year) administered at 80-120 mg/body/day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on Day 1 of the study. If the estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted, concurrently. RESULTS: Of the 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. Thirty-two of the 43 (74.4%) patients received concurrent radiotherapy. Twenty-two of the 43 (51.2%) patients completed the scheduled courses of chemotherapy. The most common reasons for withdrawal of treatment were subjective symptoms, such as nausea, anorexia, or general fatigue during the first 9 courses of treatment in 9/43 (20.9%) patients, recurrence in 7/43 (16.3%) patients, and adverse events in 5/43 (11.6%) patients. The cumulative percentage of administration for 365 days was 66.4% (95% confidence interval: 50.8-79.1%). Although grade 3 neutropenia (9.3%), leukopenia (4.7%), and diarrhea (4.7%) were observed, they were manageable. No grade 4 adverse effects were observed. CONCLUSIONS: The percentage of Japanese breast cancer patients completing the 18-course treatment and the cumulative percentage of administration for 365 days using S-1 after standard primary systemic chemotherapy were similar with the results of another study of adjuvant chemotherapy for the Japanese gastric cancer patients with no severe adverse effects. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan, and it is expected that S-1 will have a significant survival benefit in breast cancer patients. UMIN000013469.

Phase I study of weekly nab-paclitaxel combined with S-1 in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer.

We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m(2) ) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100 mg/m(2) nab-paclitaxel on days 1, 8, and 15 with 80 mg/m(2) S-1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.

Optical imaging for monitoring tumor oxygenation response after initiation of single-agent bevacizumab followed by cytotoxic chemotherapy in breast cancer patients.

PURPOSE: Optical imaging techniques for measuring tissue hemoglobin concentration have been recently accepted as a way to assess tumor vascularity and oxygenation. We investigated the correlation between early optical response to single-agent bevacizumab and treatment outcome. METHODS: Seven patients with advanced or metastatic breast cancer were treated with single-agent bevacizumab followed by addition of weekly paclitaxel. Optical imaging of patient's breasts was performed to measure tumor total hemoglobin concentration (tHb) and oxygen saturation (stO2) at baseline and on days 1, 3, 6, 8, and 13 after the first infusion of bevacizumab. To assess early metabolic response, 2-deoxy-2-(18F)-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT), 18F-fluoromisonidazole (FMISO)-PET/CT, and magnetic resonance imaging were performed at baseline and after two cycles of the regimen. RESULTS: Seven patients were grouped as responders (n = 4) and nonresponders (n = 3) on the basis of metabolic response measured by FDG-PET/CT. The responders showed remarkable tumor shrinkage and low accumulations of FMISO tracer relative to those of the nonresponders at the completion of two cycles of chemotherapy. Tumors of both groups showed remarkable attenuation of mean tHb as early as day 1 after therapy initiation. The nonresponders had lower baseline stO2 levels compared with adjacent breast tissue stO2 levels along with a pattern of steadily low stO2 levels during the observation window. On the other hand, the responders appeared to sustain high stO2 levels with temporal fluctuation. CONCLUSIONS: Low tumor stO2 level after single-agent bevacizumab treatment was characteristic of the nonresponders. Tumor stO2 level could be a predictor of an additional benefit of bevacizumab over that provided by paclitaxel.

Clinicopathological and prognostic impact of imaging of breast cancer angiogenesis and hypoxia using diffuse optical spectroscopy.

Near-infrared diffuse optical spectroscopy (DOS) imaging can non-invasively measure tumor hemoglobin concentration using high contrast to normal tissue, thus providing vascularity and oxygenation status. We assessed the clinical usefulness of DOS imaging in primary breast cancer. In all, 118 women with a histologically confirmed diagnosis of primary malignant tumor were enrolled. All participants underwent testing using time-resolved DOS before treatment initiation. Visual assessment of DOS imaging for detecting tumors was carried out by two readers blinded to the clinical data. Relative total hemoglobin (rtHb) and oxygen saturation (stO2 ) of the tumors was compared with clinicopathological variables and 10-year prognosis was calculated. Sensitivity for detecting a tumor based on the rtHb breast map was 62.7% (74/118). The sensitivity depended on T stage: 100% (7/7) for T3, 78.9% (45/57) for T2, 44.7% (17/38) for T1, and 31.3% (5/16) for Tis . Tumors showed unique features of higher rtHb with a wider range of stO2 than normal breast tissue, depending on histological type. There was a significant correlation of rtHb with tumor size, lymphatic vascular invasion, and histological grade, and of stO2 with age and tumor size. Neither rtHb nor stO2 correlated with intrinsic biomarkers such as estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2; rtHb inversely correlated with 10-year relapse-free survival and overall survival, with statistical significance. Diffuse optical spectroscopy imaging has limited utility for the early detection of breast cancer; nonetheless, the findings suggest that the degree of tumor angiogenesis and hypoxia may be associated with tumor aggressiveness and poor prognosis.

Optical imaging of tumor vascularity associated with proliferation and glucose metabolism in early breast cancer: clinical application of total hemoglobin measurements in the breast.

BACKGROUND: Near-infrared optical imaging targeting the intrinsic contrast of tissue hemoglobin has emerged as a promising approach for visualization of vascularity in cancer research. We evaluated the usefulness of diffuse optical spectroscopy using time-resolved spectroscopic (TRS) measurements for functional imaging of primary breast cancer. METHODS: Fifty-five consecutive TNM stage I/II patients with histologically proven invasive ductal carcinoma and operable breast tumors (<5 cm) who underwent TRS measurements were enrolled. Thirty (54.5%) patients underwent 18F-fluoro-deoxy-glucose (FDG) positron emission tomography with measurement of maximum tumor uptake. TRS was used to obtain oxyhemoglobin, deoxyhemoglobin, and total hemoglobin (tHb) levels from the lesions, surrounding normal tissue, and contralateral normal tissue. Lesions with tHb levels 20% higher than those present in normal tissue were defined as "hotspots," while others were considered "uniform." The findings in either tumor type were compared with clinicopathological factors. RESULTS: "Hotspot" tumors were significantly larger (P= 0.002) and exhibited significantly more advanced TNM stage (P=0.01), higher mitotic counts (P=0.01) and higher levels of FDG uptake (P=0.0004) compared with "uniform" tumors; however, other pathological variables were not significantly different between the two groups. CONCLUSIONS: Optical imaging for determination of tHb levels allowed for measurement of tumor vascularity as a function of proliferation and glucose metabolism, which may be useful for prediction of patient prognosis and potential response to treatment.

Genomic profiling shows increased glucose metabolism in luminal B breast cancer.

We had previously reported a close association between pathological response and the maximum tumor standardized uptake value (SUVmax) measured by (18)F-fluorodeoxyglucose positron emission tomography prior to chemotherapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that glucose hypermetabolism by luminal B tumors may result in chemotherapy responsiveness. Using a single-gene expression assay, TargetPrint® (Agendia) and a 70-gene expression classifier, MammaPrint® (Agendia), we divided 20 patients with ER-positive primary breast cancer into luminal A and luminal B subtypes and compared the tumor SUVmax value between the two groups. A significantly higher SUVmax was measured for luminal B tumors (n=10; mean±SD, 7.6±5.6) than for luminal A tumors (n=10; mean±SD, 2.6±1.2; p=0.01). Glucose hypermetabolism could help predict intrinsic subtyping and chemotherapy responsiveness as a supplement to ER, progesterone receptor, HER2, and Ki-67 histochemical scores.

Association of positive EBAG9 immunoreactivity with unfavorable prognosis in breast cancer patients treated with tamoxifen.

INTRODUCTION: Breast cancer is primarily a hormone-dependent tumor that is regulated by the status of the estrogen and progesterone receptors. We previously identified EBAG9 as an estrogen-responsive gene in MCF-7 human breast carcinoma cells. Upregulation of EBAG9 expression has been observed in several malignant tumors such as advanced breast cancers, indicating that EBAG9 might contribute to tumor progression. PATIENTS AND METHODS: In the present study, we generated a monoclonal antibody against EBAG9, and then performed immunohistochemical analysis of EBAG9 expression in specimens obtained from breast cancer patients treated with tamoxifen as an adjuvant therapy. RESULTS: EBAG9 immunoreactivity was detected in the cytoplasm of breast cancer cells and was significantly elevated in breast cancer samples from patients who relapsed during or after adjuvant tamoxifen treatment. Positive EBAG9 immunoreactivity was significantly correlated with poor patient prognosis. CONCLUSION: These results suggest that EBAG9 expression in tumor regions is associated with an unfavorable prognosis in breast cancer patients treated with tamoxifen.