Background:Matrix-producing carcinoma (MPC) is a rare tumor accounting for 0.1% of all breast cancers. Although MPC is usually triple-negative breast cancer, there have been few reports of preoperative chemotherapy for MPC that is considered chemotherapy-resistant. Herein, we report a case of MPC that was successfully treated with preoperative chemotherapy.Case Description:The patient was a 47-year-old woman diagnosed with right multiple breast cancer, clinical stage IIA. One of the tumors was identified as MPC and the other was invasive ductal carcinoma. The maximum tumor diameter of MPC was 3.8-cm. On immunohistochemistry, the tumor cells of MPC tested negative for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). The Ki67 index was 90%. Preoperative chemotherapy was performed. EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2) was administered every 3 weeks for a total of 4 courses, followed by 12 courses of weekly paclitaxel (80 mg/m2). Then, she underwent right skin-sparing mastectomy, sentinel lymph node biopsy, and deep inferior epigastric perforator flap reconstruction. There was no metastasis to the sentinel lymph nodes. Postoperative pathological results showed that the residual tumor of the MPC measured only 0.1 cm. On the other hand, the residual tumor of the invasive ductal carcinoma was 0.7 cm. Endocrine therapy with oral tamoxifen was initiated for the invasive ductal carcinoma. Three years after surgery, no recurrence was observed. It has been reported that prognosis was correlated with residual cancer after preoperative chemotherapy. In addition, preoperative chemotherapy is of high clinical significance for the selection of postoperative treatment.Conclusions:Although our case of MPC was successfully treated with preoperative chemotherapy, the standard of care for MPC remains uncertain. Development of a new targeted therapy for MPC is warranted.

Background/Aim: There are few models predicting breast cancer prognosis among patients receiving neoadjuvant chemotherapy (NAC) for estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (luminal) breast cancer. We examined whether biological features (BFs) of residual tumors are prognostic factors following NAC. Patients and Methods: We enrolled patients with remnant tumors following NAC for luminal breast cancer and evaluated clinical stage, pathological stage, BFs prior to NAC, and BFs following NAC as prognostic factors. BFs were divided into high and low risk using the previously reported YR-IHC4 model calculated according to ER, progesterone receptor (PgR), HER2, and the proliferation marker Ki-67. Results: A total of 57 patients were enrolled in the current study. We observed a statistically significant difference in relapse-free survival (RFS) between the BF risk categories via YR-IHC4 predictions following NAC (p=0.044). The 5-year RFS rates of the BF low- and high-risk groups following NAC were 84.2% and 52.5%, respectively. Conclusion: BFs of residual tumors following NAC may be important prognostic factors in luminal breast cancer.

Background/Aim: Oncotype DX recurrence score (RS) for breast cancer is a useful tool for determining chemotherapy indication but it is expensive and time-consuming. We determined whether four immuno-histochemical markers, namely human epidermal growth factor 2 (HER2), estrogen receptor (ER), progesterone receptor (PgR), and Ki-67, are predictive of an RS ≥26 in Japanese patients. Patients and Methods: The study included 95 Japanese patients evaluated for RS. A predictive model was created using logistic regression analysis. Results: The discriminant function was calculated as follows: p=1/{1+exp [−(4.611+1.2342×HER2−0.0813×ER− 0.0489 ×PgR+0.0857×Ki67)]}. Using a probability of 0.5 as the cutoff, the accuracy, sensitivity, specificity, positive predictive and negative predictive values were 90.5%, 72.2%, 94.8%, 76.4% and 93.5%, respectively. Conclusion: The model had a high negative predictive value in predicting RS ≥26 in Japanese patients, indicating that Oncotype DX testing may be omitted in patients with a negative result according to the predictive model.

Hypoxia is a key driver of cancer progression. We evaluated the prognostic impact of 18F-fluoromisonidazole (FMISO) prior to treatment in patients with breast cancer.

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.

and check for possible sequencing errors. We detected 29 somatic mutations, including a recurrent somatic R625C mutation in SF3B1 (frequency, 43.9%). Hotspot neomorphic SF3B1 mutations have been identified in uveal melanoma and subsequently in mucosal melanoma [1, 4]. SF3B1 encodes a component of the spliceosome that regulates RNA splicing and is the most frequently mutated component of the spliceosome in cancer [5]. Dysregulated alternative splicing plays important roles in tumourigenesis and resistance to therapy [5]. SF3B1 mutation induces subtle but broad changes in gene expression and splicing across multiple pathways in chronic lymphocytic leukaemia patients [6]. Such patients have been shown to have faster disease progression and poorer prognosis. SF3B1 is mutated in 18.6% of uveal melanoma, and less than 1% in cutaneous melanoma [1]. We have performed whole-exome sequencing in two mucosal melanoma patients including a 43-year-old man with metastatic melanoma from gingival mucosal melanoma. Previous data [1, 4, 7] and our own data reveal recurrent somatic SF3B1 mutations in 15 of 42 (35.7%) mucosal melanoma patients, suggesting that neomorphic SF3B1 mutations are critical for the occurrence and development of mucosal melanomas. SF3B1 mutation is possibly the driver mutation in mucosal melanoma. In uveal melanoma, GNAQ and GNA11, with somatic mutations, are the driver genes, and somatic BAP1, SF3B1, and EIF1AX mutations occur during tumour progression [8]. GNAQ and GNA11 mutations are mutually exclusive with each other, and BAP1, SF3B1, and EIF1AX mutations occur in an almost mutually exclusive manner [8]. Mutation of the driver genes GNAQ and GNA11 is not associated with prognosis, whereas the secondary mutated genes of BAP1, SF3B1, and EIF1AX are prognostically significant [8]. BAP1 mutation is considered a poor prognostic factor, while SF3B1 and EIF1AX mutations are considered good prognostic factors [8]. Future studies should focus on patients with mucosal melanoma in order to evaluate the contribution of neomorphic SF3B1 mutation to tumorigenesis and investigate why mucosal melanoma is associated with a poor prognosis.

Purpose: Eribulin mesylate (eribulin) is a first-in-class halichondrin B-based microtubule dynamics inhibitor. To understand the mechanism of vascular remodeling of eribulin, we compared optical hemodynamic and blood biomarker changes between eribulin and bevacizumab. 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. Diffuse optical spectroscopic imaging (DOSI) measured tissue concentrations of oxy-hemoglobin (O2Hb), deoxy-hemoglobin (HHb), total hemoglobin (tHb) and oxygen saturation (SO2) of breast tumors before and day 7 after the first infusion. Peripheral blood samples were obtained from the patients to measure plasma concentration of VEGF, bFGF, FLT-3L, EGF, G-CSF, TNFα, IL1b, IL4, IL6, IL8, IL10, IL12p40, and TGF-β1. Results: Baseline DOSI measurement of all 29 patients (eribulin, n = 14 and bevacizumab, n = 15) revealed significantly higher tumor concentrations of O2Hb, HHb, and tHb than that in the normal breast tissue. Eribulin significantly decreased 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 and tHb. The blood biomarker study revealed that both eribulin and bevacizumab decreased plasma concentrations of VEGF and bFGF, but only eribulin suppressed the plasma concentration of TGF-β1. Conclusions: Optical imaging technology revealed that eribulin, but not bevacizumab, induced tumor reoxygenation after the start of infusion. Eribulin had a potent anti-angiogenic properties as well as bevacizumab, while suppression of TGF-β1 observed by only eribulin could be associated with remodeling of the microvasculature through suppression of activated stromal cells. Citation Format: Ueda S, Saeki TS, Takeuchi H, Shigekawa T, Yamane T, Kuji I, Osaki A. Eribulin induces vascular remodeling and reoxygenation in advanced breast cancer patients: A comparative study with bevacizumab [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-01.

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.

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 (O 2 Hb) and deoxyhaemoglobin (HHb), and oxygen saturation (SO 2 ) 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 O 2 Hb and HHb than that in the normal breast tissue. After eribulin treatment, DOSI revealed a significant decrease in HHb concentration and increased SO 2 during the observation period. This trend was not observed for bevacizumab. Instead, bevacizumab significantly decreased the concentration of O 2 Hb. 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- β 1. Conclusions: Eribulin, but not bevacizumab, treatment increased tumour SO 2 . Suppression of TGF- β 1 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.

The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT 3 ) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT 3 receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT 3 receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.

Neoadjuvant chemotherapy (NAC) is one of the main therapies for patients with local advanced breast cancer. CT and MRI have been used in combination with pathological examination in order to evaluate the efficacy of NAC. We present a case that showed discrepancies between the pathological findings and those of imaging analysis after NAC. We administered NAC to a patient with stage IIIB locally-advanced breast cancer. NAC showed remarkable drug efficacy. Clinical tumor response evaluated by CT and MRI showed a residual tumor. However, the pathological tumor response following NAC was grade 2b according to criteria of the Japanese Breast Cancer Society. Inaccurate determination of a residual tumor by MRI (a residual tumor diagnosed by MRI but a pathological complete response diagnosed by pathological examination) can occur occasionally.

Background: Diffuse optical spectroscopic imaging (DOSI) can be exploited as a marker of tumor blood volume quantified by tissue hemoglobin (tHb) concentration. In DOSI, frequent measurement is possible for breast cancer patients because of its non-invasiveness. The tHb concentration determined by DOSI is expected to be a new biomarker for prediction of breast cancer response to neoadjuvant chemotherapy (NAC). Purpose: Our objective is to determine whether early change of tumor tHb concentration predicts pathological complete response (pCR) to NAC in patients with operable breast cancer. Methods: In a prospective study, one hundred patients with primary breast cancer were enrolled for primary objective analysis. The regimens of NAC were according to the standard of care. Patients underwent sequential scans using DOSI at baseline, after 1st course and 2nd course of chemotherapy. The mean value of tHb (tHbmean) concentration of the targeted lesion was measured and the percentage change in tHbmean (ΔtHbmean) concentration was calculated. Receiver operating curve analysis demonstrated diagnostic performance of DOSI for predicting a pCR. Results: In interim analysis, it was regarded as a good outcome that area under the curve (AUC) for ΔtHbmean after 1nd course was 0.797 (SE 0.104, 95%CI 0.633-0.911), and after 2st course was 0.867 (SE 0.06, 95%CI 0.715-0.956). Conclusion: DOSI could predict accurately a pCR to neoadjuvant chemotherapy in patients with primary breast cancer. Citation Format: Ogura H, Yoshizawa N, Ueda S, Hosokawa Y, Matsunuma R, Tochikubo J, Nasu H, Shigekawa T, Takeuchi H, Osaki A, Saeki T, Yoshimoto K, Ohmae E, Suzuki T, Ueda Y, Yamashita Y, Sakahara H. Near-infrared diffuse optical imaging for early prediction to neoadjuvant chemotherapy in patients with primary breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-03-06.

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.

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.

165 Background: Advanced breast cancer can respond to S-1. Other oral fluoropyrimidine-based regimen, tegafur-uracil (UFT) was proven to be effective as adjuvant chemotherapy in Japanese breast cancer patients. Adjuvant chemotherapy with S-1 was useful in gastric cancer patients and S-1 with concurrent radiotherapy was safe and effective in several kinds of cancer patients. We tested S-1 and concurrent radiotherapy as adjuvant therapy in curatively resected breast cancer patients after standard primary systemic chemotherapy. Methods: Adjuvant chemotherapy with S-1 consisted of eighteen courses (2-week administration and 1-week withdrawal), at 80-120 mg/body per day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on day1 of the study (a fractional daily dose of 1.8 Gy, up to a total dose of 50.4Gy). If estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted concurrently. Results: Among 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. 32 patients (74.4%) received concurrent radiotherapy. 22 patients (51.2%) completed the scheduled courses of chemotherapy. The most common reason for withdrawal of treatment was the request to discontinue in 8 patients (38.1%) between 6 courses of the beginning due to subjective symptoms, such as anorexia. It was followed by the detection of recurrence in 7 patients (33.3%). Among 36 patients without recurrence, the planned courses of S-1 were administered to 22 patients (61.1%), and the cumulative rates of administration for 365 days were 66.4% (95%CI: 50.8-79.1%). Although grade 3 neutropenia (8.9%), leukopenia (4.4%), and diarrhea (4.4%) were observed, they were manageable, and no grade 4 adverse effects appeared. Conclusions: Except for a relative many withdrawal of treatment due to subjective symptoms in early courses, adjuvant chemotherapy with S-1 and concurrent radiotherapy have an acceptable toxicity profile, and it seems feasible. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan.

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.