Takashi Kuwayama

Primary analysis of a randomized phase II, multicenter trial: Neoadjuvant weekly nab-paclitaxel 100mg/m2 followed by FE100C compared with docetaxel 75mg/m2 followed by FE100C for early breast cancer in Japan.

136 Background: Nanoparticle Albumin-Bound Paclitaxel (nab-PTX) is a new solvent free taxane-based anticancer drug. According to CA024 trial, nab-PTX 100mg/m2 demonstrated superior response to docetaxel (DTX) in patients with metastatic breast cancer. Besides, nab-PTX 100mg/m2 was less toxicity. In operable breast cancer, GeparSepto study was reported that the pCR rate were significantly higher with nab-PTX 125/150 mg/m2 compared to paclitaxel. We planned the randomized parallel design phase II trial to evaluate nab-PTX 100mg/m2in early breast cancer. METHODS Stage II-III HER2-negative breast cancer patients were included in this trial and received either 4 cycles of DTX (75 mg/m2 day1) q 3 w or 4 cycles of nab-PTX (100 mg/m2 day1/8/15) q4w followed by 4 cycles of FE100C. The primary end point is pCR (ypT0/is ypN0) rate, and the secondary end points are response rate, histological effect of treatment, breast conservation rate, and toxicity. RESULTS Between March 2011 to March 2014, 152 eligible patients were enrolled at 6 centers (75 pts were allocated for nab-PTX). Baseline characteristics were well balanced; median age was 51/49 years (DTX/nab-PTX), 61/61% of the patients with ER positive, 38/36% triple negative breast cancer, 57/65% Ki67 > 20%. Clinically response rate was similar to each drug. (53/57%) The pCR rate was 12/17% (p = 0.323). In TNBC group, the pCR rate was 28/30% (p = 0.866). In Ki67 > 20% group, the pCR rate was significantly higher, 16/48% (p = 0.021) with nab-PTX arm. The most common grade3-4 adverse event was neutropenia, which was observed in 40/36% of cases. Non-hematological adverse events of any grade were; 34/32% myalgia (DTX/nab-PTX), 42/35% arthralgia, 55/65% peripheral sensory neuropathy. No Grade3-4 peripheral sensory neuropathy was observed in nab-PTX arm. Infusion reaction of DTX occurred in 1 patient. CONCLUSIONS In this initial effectively analysis, neoadjuvant weekly nab-paclitaxel 100mg/m2 were promising drug in HER2-negative operable breast cancer patients. Larger studies will be needed to evaluate neoadjuvant weekly nab-paclitaxel compared with DTX. CLINICAL TRIAL INFORMATION 000005388.

A genome-wide association study identifies three novel genetic markers for response to tamoxifen: A prospective multicenter study

Purpose Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen. Experimental design We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study. Results The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10−6, 1.64 x 10−5, and 9.77 x 10−6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10−12), suggesting the cumulative effect of the three SNPs. Conclusion We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.

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.