Teruo Yamauchi

Potential role of pNF-H, a biomarker of axonal damage in the central nervous system, as a predictive marker of chemotherapy-induced cognitive impairment

Purpose: Chemotherapy-induced cognitive impairment (CICI) is a clinically significant problem. Previous studies using magnetic resonance imaging indicated structural changes in the cerebral white matter of patients with CICI. Phosphorylated neurofilament heavy subunit (pNF-H), a major structural protein in axons, was recently reported to be elevated in the serum of patients with some central nervous system disorders. We performed a cross-sectional analysis of neuropsychological test results and serum pNF-H levels in patients undergoing adjuvant chemotherapy for breast cancer. Our hypothesis was that CICI is accompanied by axonal damage that can be detected by elevated serum pNF-H levels. Experimental Design: Seventy-six patients with early breast cancer in various phases of treatment (naïve to chemotherapy; after one, three, or seven cycles of chemotherapy; or with a history of chemotherapy) were assessed by self-administered neuropsychological tests and a single pNF-H measurement. The χ2 and Mann–Whitney tests were used for statistical analysis. Results: Increased pNF-H levels were observed in 28.8% of the patients who underwent chemotherapy, but in none of the chemotherapy-naïve patients or patients with a history of chemotherapy. The pNF-H–positive rate increased significantly in proportion to the number of chemotherapy cycles (one cycle, 5.0%; three cycles, 31.6%; seven cycles, 55.0%; P < 0.05). No significant differences in neuropsychological test results were observed among the groups. Conclusions: The serum pNF-H level in patients undergoing chemotherapy for breast cancer increased in a cumulative dose-dependent manner, suggesting its potential application as a biomarker of neural damage after chemotherapy. Clin Cancer Res; 21(6); 1348–52. ©2015 AACR.

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.

Actionable Gene Alterations in an Asian Population With Triple-Negative Breast Cancer

Purpose It has been suggested that the biological characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to show a higher incidence in Japan than in the US. However, most genomic studies of these tumors are from Western countries and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gather data primarily from non-Asian patients. Materials and Methods We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes on Japanese TNBC patients (N=53) and compared the results to independent data obtained from TCGA (N=123). Results Driver alterations were identified in 51 out of 53 Japanese patients (96%). Although the overall alteration spectrum of Japanese patients was similar to that of the TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutation burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35/53) of Japanese patients, as well as 66.7% (82/123) of the TCGA cohort, had alterations in at least one actionable gene targetable by an FDA-approved drug. Conclusion Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

Patients' Perspectives on Creating a Personal Safety Net During Chemotherapy.

Nurses are critical to the physical management and psychological support of patients undergoing chemotherapy, which is a vulnerable time for many. This article presents the results of a qualitative study intended to explore the experience of Japanese patients with breast cancer during chemotherapy, including the finding that participants created personal safety nets in physical, emotional, and social contexts that helped them to gain confidence in their ability to exert control over their lives. Understanding each patients personal safety net allows nurses to support their patients in maintaining and improving their function and well-being.

Systemic and Targeted Therapy

Historically, single-modality therapy failed to control inflammatory breast cancer (IBC), a very aggressive and rare type of advanced breast cancer with poor prognosis. With the introduction of multimodality treatment (primary and adjuvant systemic therapy, surgery, and radiation therapy), the prognosis of inflammatory breast cancer (IBC) has significantly improved. Current standard treatment of IBC consists of primary systemic therapy, including trastuzumab for HER-2/neu overexpressing IBC, followed by surgery with mastectomy and complete axillary lymph node dissection, and subsequently radiation therapy.

ACE inhibitors/ARB and the risk of breast cancer recurrence after surgery in Japanese population: A pilot study.

52 Background: Angiotensin II can work as a growth promoter via angiotensin II type1 receptor (AT1R). In an in vivo study, Angiotensin Converting Enzyme Inhibitor (ACEI)/Angiotensin Receptor Blocker (ARB) down regulates vascular endothelial growth factor and activates apoptosis pathway through AT1R. In some clinical studies, the efficacy of ACEI/ARB to cancer patients has been investigated; however, the results are various. This has not been examined in Asian population. We investigated breast cancer patients in a single institution if the recurrence rate is related to ACEI/ARB use. METHODS This retrospective study will evaluate disease-free survival (DFS) for Japanese patients who were diagnosed with invasive breast cancer and had curative surgery between January 2004 and December 2006 at St Lukes International Hospital. We will compare DFS of two groups with and without ACEI/ARB use. DFS is defined as the interval between curative surgery and the recurrence of breast cancer. Recurrence of disease was confirmed by radiographically or pathologically. Patients who took ACEI/ARB are defined as those who had taken them for at least 6 months after initial diagnosis. The following patient data will be extracted from their medical records; age, stage, body mass index, menopausal status, biomarker status (ER, PgR, and HER2), usage of bisphosphonate, usage of statin, diabetes, surgical procedure. RESULTS A total of 1,163 patients were analyzed. 76 were ACEI/ARB user and 1,087 were non-user. The recurrence rate of ACEI/ARB users was 17.1% (13/76). In comparison, that of non-users was 12.2% (133/1,087). The odds ratio (OR) was 1.480 (95 % CI: 0.793-2.762 p=0.218). Kaplan-Meier analysis did not show a significant difference between them (log-rank test p=0.194). CONCLUSIONS Our study is the first one to evaluate the efficacy of ACEI/ARB in breast cancer recurrence among Asian population. Recurrence rate did not differ in the two groups although molecular biology suggested antitumor effect of ACEI/ARB. We will further explore if any confounding factors lie between the two groups, and plan to conduct a prospective study if ACEI/ARB exhibits antiproliferative effect in postoperative cancer patients.