Hiromitsu Jinno

A phase II trial of capecitabine and docetaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) as preoperative treatment in women with stage II/III breast cancer

BACKGROUND Capecitabine (X) and docetaxel (T) have demonstrated a synergistic effect in preclinical models and a survival benefit in metastatic breast cancer. This studys purpose was to determine the efficacy of X and T followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) in the preoperative setting. PATIENTS AND METHODS Patients with stage II/III breast cancer received four cycles of XT (capecitabine 1650 mg/m(2) on days 1-14 and docetaxel 60 mg/m(2) on day 8 every 3 weeks), followed by four cycles of FEC (5-fluorouracil 500 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 500 mg/m(2) on day 1 every 3 weeks). Primary end points were the pathological complete response (pCR) rate and adverse drug reactions. RESULTS Seventy-four patients were enrolled and 71 patients were assessable for clinical and pathological responses. The overall response rate was 91.5%. The pCR rate was 14.1% (10 of 71). Grade 3/4 neutropenia was observed in 32.4% of patients. The most common grade 3/4 non-hematologic adverse event was hand-foot syndrome, observed in 11.3% of patients. With 29 months median follow-up, 2-year disease-free survival was estimated 85% for all patients. CONCLUSION These data indicate that the sequential combination of XT followed by FEC is a well-tolerated, effective neoadjuvant treatment of stage II/III breast cancer.

Biological markers of invasive breast cancer

Biological markers for breast cancer are biomolecules that result from cancer-related processes and are associated with particular clinical outcomes; they thus help predict responses to therapy. In recent years, gene expression profiling has made the molecular classification of breast cancer possible. Classification of breast cancer by immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 and Ki-67 is standard practice for clinical decision-making. Assessments of hormone receptor expression and human epidermal growth factor receptor 2 overexpression help estimate benefits from targeted therapies and have greatly improved prognoses for women with these breast cancer types. Although Ki-67 positivity is associated with an adverse outcome, its clear identification is an aid to optimal disease management. Standardization of testing methodology to minimize inter-laboratory measurement variations is a remaining issue. Multi-gene assays provide prognostic information and identify those most likely to benefit from systemic chemotherapy. Incorporating molecular profiles with conventional pathological classification would be more precise, and could enhance the clinical development of personalized therapy in breast cancer.

The Japanese Breast Cancer Society clinical practice guideline for surgical treatment of breast cancer, 2015 edition

In the Clinical Practice Guideline for Surgical Treatment of Breast Cancer, clinical questions (CQs) were divided into 6 categories: (1) breast-conserving therapy (BCT); (2) axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB); (3) less invasive treatments (endoscopic surgery and non-surgical ablation); (4) breast reconstruction; (5) surgical treatment for advanced and metastatic breast cancer; and (6) others. Major revisions to the 2015 edition were as follows: positive surgical margins for breast-conserving surgery were defined as ink on invasive or in situ cancer in CQ3; SLNB using indocyanine green (ICG) fluorescence imaging was newly described in CQ10; and recommendations were updated for CQ18 and 28. Breast-conserving therapy

Self-rated cognitive functions following chemotherapy in patients with breast cancer: a 6-month prospective study

Purpose The purpose of the study was to evaluate subjective (self-rated), family-rated, and objective (researcher-rated) cognitive functions in patients with breast cancer after chemotherapy. Method We conducted a prospective study to trace self-rated cognitive functions in 30 patients with breast cancer at the completion of chemotherapy (T0) and 6 months later (T1). Subjective cognitive functions were assessed with Cognitive Failures Questionnaire (CFQ), Dysexecutive Questionnaire (DEX-S), and Everyday Memory Checklist (EMC-S) for attention, executive function, and episodic memory, respectively. Their family members also completed DEX-I and EMC-I for executive function and episodic memory, respectively. We also examined objective cognitive functions. Self-rated cognitive functions were compared with the normative data. They were compared between T0 and T1. We calculated correlation coefficients between self-rated and other cognitive functions. Results At T0, 6 (20.0%) and 2 (6.7%) participants showed higher DEX-S and EMC-S scores than the normative data, respectively, while no participant had abnormal CFQ scores. At T1, DEX-S and EMC-S scores were normalized in 3 (50.0%) and 2 (100.0%) participants, respectively. No participant showed increases in CFQ scores. No changes were found in objective cognitive functions from T0 to T1. DEX-S and DEX-I or EMC-S and EMC-I scores were correlated at both T0 and T1, which did not survive multiple corrections. There was no association between subjective and objective cognitive functions. Conclusion Impairments in subjective cognition may be transient after chemotherapy in patients with breast cancer. Furthermore, patients and their families appear to share similar prospects on their cognitive functions.

Technical feasibility of sentinel lymph node biopsy in patients with ipsilateral breast tumor recurrence and previous axillary surgery

INTRODUCTION The role of sentinel lymph node biopsy (SLNB) in patients with ipsilateral breast tumor recurrence (IBTR) remains to be elucidated. The aim of this study was to evaluate feasibility and validity of SLNB in patients with IBTR. METHODS A prospective database of 1172 patients with clinically node-negative breast cancer who underwent SLNB from January 2005 to December 2013 at Keio University Hospital was analyzed and 35 patients with IBTR underwent SLNB. Sentinel lymph nodes (SLNs) were detected using a combined method of blue dye and radioisotope or indocyanine green fluorescence in cases with failure of identification by blue dye and radioisotope. RESULTS Twenty-two patients had previous SLNB, eight had previous axillary lymph node dissection (ALND), and five had no previous axillary surgery. Overall, SLNs were successfully identified in 28 (80.0%) of 35 patients. The identification rate in patients with previous SLNB, ALND and no axillary surgery was 81.8% (18/22), 75% (6/8) and 80% (4/5), respectively (P = 0.52). Aberrant drainage outside the ipsilateral axilla was found more frequently in patients with previous ALND compared with SLNB and no axillary treatment (37.5% vs. 4.5% vs. 0%, P = 0.048). No axillary recurrence was observed after median follow-up of 40.3 months from the second surgery for IBTR. CONCLUSIONS SLNB is a technically feasible and valid procedure for staging and treatment of regional lymph nodes in patients with IBTR.

Dynamic changes in CD44v-positive cells after preoperative anti-HER2 therapy and its correlation with pathologic complete response in HER2-positive breast cancer

Chemotherapy has been reported to increase the proportion of cancer stem cells (CSCs) and to promote epithelial-mesenchymal transition (EMT) phenotype changes. Anti-HER2 therapy may provide a strategy for eliminating CSC and EMT, which contribute to therapeutic resistance. No study has determined the changes in the quantity or characteristics of CSCs or circulating tumor cells (CTCs) with EMT phenotype during preoperative anti-HER2 therapy, and whether these changes correlate to response to dual anti-HER2 therapy. In a prospective clinical trial to evaluate pharmacodynamic biomarkers, 18 patients with operable primary HER2-positive breast cancer received dual anti-Her2 preoperative therapy with trastuzumab and lapatinib with paclitaxel. Proportions of tumor cells with CSC characteristics and EMT markers in CTCs were estimated at baseline, after 6 and 18 weeks of preoperative therapy to determine the quantitative cutoff value to predict pathologic complete response (pCR). Out of 18 patients, 8 (44%) had a pCR; 5 of these 8 patients (62%) were positive for CD44v at baseline and none were positive on the 6-week biopsy. In contrast, 6 of the 10 patients without pCR exhibited persistent levels, or enrichment of CD44v proportion and expression at 6 and 18 weeks (p=0.0128). Other biomarkers were not statistically significant predictors of pCR. Enrichment of CD44v-positive tumor cells after dual anti-HER2 therapy alone may predict poor response to dual anti-HER2 therapy plus chemotherapy.

The Noninvasive Treatment for Sentinel Lymph Node Metastasis by Photodynamic Therapy Using Phospholipid Polymer as a Nanotransporter of Verteporfin

Aim. The usefulness of photodynamic therapy (PDT) for treating sentinel lymph node (SLN) metastasis was evaluated. Materials and Methods. Verteporfin, a hydrophobic photosensitizer, forms a soluble aggregate with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB). The concentrations of verteporfin were determined by measuring the fluorescence emitted at 700 nm. Seven days after the inoculation of A431 cells at the forearm of BALB/c nude mice, PMB-verteporfin was injected at dorsum manus and 75 J of light energy was delivered for 1 minute. Fifty-three mice were randomly assigned to the combination of PMB-verteporfin injection and light exposure, light exposure alone, PMB-verteporfin injection alone, and no treatment groups. Ten days after PDT, brachial lymph nodes, which were considered as SLNs, were harvested and evaluated. Results. The concentration of verteporfin in SLN was significantly higher than other organs. The combination of PMB-verteporfin injection and light exposure group significantly reduced the SLN metastasis (13%) comparing with no treatment group (52%), light exposure alone group (57%), and PMB-verteporfin injection alone group (46%). Conclusions. These data suggested that PDT using PMB as a nanotransporter of verteporfin could be a minimally invasive treatment of SLN metastasis in breast cancer and represent a potential alternative procedure to SLNB.

Exosome‑encapsulated microRNA‑223‑3p as a minimally invasive biomarker for the early detection of invasive breast cancer

Patients diagnosed preoperatively with ductal carcinoma in situ (DCIS) breast cancer have the potential to develop invasive ductal carcinoma (IDC). The present study investigated the usefulness of exosome-encapsulated microRNA-223-3p (miR-223-3p) as a biomarker for detecting IDC in patients initially diagnosed with DCIS by biopsy. The potential association between miR-223-3p and clinicopathological characteristics was examined in patients with breast cancer. Exosomes of 185 patients with breast cancer were separated from plasma by ultracentrifugation. Initially a microRNA (miRNA) microarray was examined to reveal the invasion specific miRNAs using exosomes collected from 6 patients with breast cancer, including 3 DCIS patients, 3 IDC patients and 3 healthy controls. In the miR microarray analysis the miR-223-3p levels of IDC patients demonstrated the highest fold-change compared with those in the DCIS patients and healthy controls. The potential of miR-223-3p for cell proliferation and cell invasion were examined in vitro using MCF7 cells transfected with the miR-223-3p gene. MCF7 cells transfected with the miR-223-3p gene significantly promoted cell proliferation and cell invasive ability (P<0.05). The plasma exosomal miR-223-3p levels of the other 179 patients with breast cancer and 20 healthy controls were measured using TaqMan miR assays. The exosomal miR-223-3p levels of the patients with breast cancer were significantly increased compared with the healthy controls (P<0.01). A statistically significant association was observed between the exosomal miR-223-3p levels and histological type, pT stage, pN stage, pathological stage, lymphatic invasion and nuclear grade (P<0.05). The exosomal miR-223-3p levels of IDC patients (stage I) and upstaged IDC patients (stage I) were significantly higher compared with the DCIS patients (P<0.05). These results suggest that exosomal miR-223-3p may be a useful preoperative biomarker to identify the invasive lesions of DCIS patients diagnosed by biopsy. In addition, plasma exosome-encapsulated miR-223-3p level was significantly associated with the malignancy of breast cancer.

Efficacy and Safety of the Skin Adhesive EpinexusTM in Surgical Patients

This single-center, randomized, and controlled intervention study compared an acrylate skin adhesive, EpinexusTM (Mitsui Chemicals, Inc., Tokyo) with Dermabond AdvancedR (Ethicon, Inc., Somerville, New Jersey). The primary endpoint was cosmetic outcome at 52 weeks after treatment (Manchester Scar Scale), and the secondary endpoints were cosmetic outcome at 4 and 26 weeks after treatment (Manchester Scar Scale), wound closure, and usability. We evaluated 59 patients (29 cases and 30 controls). Failures and adverse events were also evaluated, and 8 adverse events (5 cases and 3 controls) were reported (epidermolysis, n = 4; contact dermatitis, n = 1; eczema, n = 1; and surgical wound dehiscence, n = 2). No difference was observed between groups in cosmetic outcome at 52 and 24 weeks; however, at 4 weeks, cases showed better cosmetic outcome compared with controls. With regard to usability, the treatment duration and application time were significantly longer with EpinexusTM, and ease of application was significantly better with Dermabond AdvancedR.

Mindfulness-based cognitive therapy for Japanese breast cancer patients-a feasibility study

Objectives Mindfulness-based intervention has been receiving growing attention in cancer care. This study aimed to examine feasibility and to preliminary explore effectiveness of mindfulness-based cognitive therapy (MBCT) in Japanese breast cancer patients, and to explore possible modification of the program so that it fits better with this population. Methods Twelve participants with diagnosis of Stage I-III breast cancer received an eight session, weekly MBCT intervention in a group therapy format. The participants were followed up until 3 months after the completion of the program. Results All the participants completed the program with high attendance rate (mean number of attended sessions = 7.7). Significant improvement in anxiety (Hospital Anxiety and Depression Scale (HADS) - anxiety subscale; effect size Cohens d = 0.88, P < 0.05), trauma-related psychological symptoms (Impact of Event Scale-revised; d = 0.64, P < 0.01) and quality of life (Functional Assessment of Cancer Therapy-Breast Cancer: FACT-B; d = 0.72, P < 0.01), and trend-level improvement in depression (HADS - depression subscale; d = 0.53, P = 0.054) were observed. Qualitative analyses suggested the program may be beneficial for alleviating fear of cancer recurrence and for increasing spiritual well-being. Some recommended modification of the program was indicated from the post-intervention interviews. Conclusions Mindfulness-based cognitive therapy was well accepted by Japanese breast cancer patients and yielded favorable effect on their psychological status and quality of life. Further effectiveness study in a randomized-control design is warranted.