Hiroko Shimada

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

BackgroundNear-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.MethodsFifty-five consecutive TNM stageI/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.ConclusionsOptical 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.

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 patients 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.

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.

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 18F-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.

Intracellular hypoxia measured by 18 F-fluoromisonidazole positron emission tomography has prognostic impact in patients with estrogen receptor-positive breast cancer

BackgroundHypoxia is a key driver of cancer progression. We evaluated the prognostic impact of 18F-fluoromisonidazole (FMISO) prior to treatment in patients with breast cancer.MethodsForty-four patients with stage II/III primary breast cancer underwent positron emission tomography/computed with 18F-fluorodeoxyglucose (FDG-PET/CT) and FMISO. After measurement by FDG-PET/CT, the tissue-to-blood ratio (TBR) was obtained using FMISO-PET/CT. FMISO-TBR was compared for correlation with clinicopathological factors, disease-free survival (DFS), and overall survival (OS). Multiplex cytokines were analyzed for the correlation of FMISO-TBR.ResultsTumors with higher nuclear grade and negativities of estrogen receptor (ER) and progesterone receptor had significantly higher FMISO-TBR than other tumors. Kaplan-Meier survival curves showed that patients with a higher FMISO-TBR (cutoff, 1.48) had a poorer prognosis of DFS (p = 0.0007) and OS (p = 0.04) than those with a lower FMISO-TBR. Multivariate analysis indicated that higher FMISO-TBR and ER negativity were independent predictors of shorter DFS (p = 0.01 and 0.03). Higher FMISO-TBR was associated with higher plasma levels of angiogenic hypoxic markers such as vascular endothelial growth factor, transforming growth factor-α, and interleukin 8.ConclusionsFMISO-PET/CT is useful for assessing the prognosis of patients with breast cancer, but it should be stratified by ER status.Trial registrationUMIN Clinical Trials Registry, UMIN000006802. Registered on 1 December 2011.

Correction to: Intracellular hypoxia measured by F-18 fluoromisonidazole positron emission tomography has prognostic impact in patients with estrogen-receptor positive breast (BRCR-D17-00693)

After the publication of this article [1], we noticed that in Fig. 2, the survival curve images (C and D, lower panel) were incorrect. The corrected Fig. 2 is presented below. The correction does not affect in any our results and conclusions.

Fibrotic focus: An important parameter for accurate prediction of a high level of tumor-associated macrophage infiltration in invasive ductal carcinoma of the breast

Our group and others have previously reported that a fibrotic focus is a very useful histological factor for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 258 cases of invasive ductal carcinoma into those with and those without a fibrotic focus to investigate whether the presence of a fibrotic focus was significantly associated with the degree of tumor‐associated macrophage (CD68, CD163 or CD204‐positive) infiltration or whether the presence of tumor‐associated macrophage infiltration heightened the malignant potential of invasive ductal carcinoma with a fibrotic focus. Multiple regression analyses demonstrated that a fibrotic focus was the only factor that was significantly associated with a high level of CD68‐, CD163‐ or CD204‐positive tumor‐associated macrophage infiltration. The combined assessment of the presence or absence of a fibrotic focus and a high or a low level of CD204‐positive tumor‐associated macrophage infiltration clearly demonstrated that CD204‐positive tumor‐associated macrophage infiltration had a significant prognostic power only for patients with invasive ductal carcinoma with a fibrotic focus in multivariate analyses; CD204‐positive tumor‐associated macrophages might only exert a significant effect on tumor progression when a fibrotic focus is present within the invasive ductal carcinoma of the breast.

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.

321PCLINICOPATHOLOGICAL CHARACTERISTICS AND OUTCOMES OF BREAST CANCER PATIENTS WITH COLLAGEN DISORDERS

ABSTRACT Aim: Treatment for breast cancer with collagen disorder is complicated due to the use of steroids and immunosuppressants, and its clinical course is thus interesting. We herein report the results of an investigation on breast cancer in women with collagen disorders. Methods: The subjects were 25 patients with collagen disorders among those diagnosed with breast cancer who had received treatment at our hospital from 2003 to 2011. We examined clinicopathological factors, treatment, recurrence-free survival rates and overall survival rates. Results: The mean age was 57 years (31-84 years), and the clinical stage was I in14 cases, II in 8, and III in 3. The status of lymph node metastasis was N0 in 15 cases and N1 in 10. Concomitant collagen disorders included rheumatoid arthritis in 11 cases, systemic lupus erythematosus in 4, dermatomyositis, mixed connective tissue disease, and Sjogrens syndrome in 2 cases each, and scleroderma and adult onset Stills disease in 1 case each. The status of hormone receptors (HR) and human epidermal growth factor 2 (HER2) expression was as follows: ER(+)HER2(-) in 18 cases (72.0%), HER(+)HER2(+) in 2 (8.0%), HR(-)HER2(+) in 1 (4.0%), triple negative in 4 (16.0%). While there was no bias in clinicopathological factors, 21 of the 25 cases (84.0%) had received steroids and/or immunosuppressants for collagen disorders. After a median observation period of 47 months, the recurrence-free survival and overall survival rate was 64.5% and 80.7%, respectively, lower than those of breast cancer patient who underwent surgery at approximately the same time (n = 476, recurrence-free survival rate: 85.3%, overall survival rate: 94.3%. Conclusions: In breast cancer cases with collagen disorders, steroids and/or other immunosuppressants were frequently administered, and both recurrence-free survival and overall survival rates were comparatively low. Disclosure: All authors have declared no conflicts of interest.