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Cyclohexanecarboxylate (CHCA) is formed by oxidative microbial degradation of n-alkylcycloparaffins and anaerobic degradation of benzoate, and also known to be a synthetic intermediate or the starter unit of biosynthesis of cellular constituents and secondary metabolites. Although two degradation pathways have been proposed, genetic information has been limited to the β-oxidation-like pathway. In this study, we identified a gene cluster, designated chcC1XTC2B1B2RAaAbAc, that is responsible for the CHCA aromatization pathway in Sinomonas (formerly Corynebacterium) cyclohexanicum strain ATCC 51369. Reverse transcription-PCR analysis indicated that the chc gene cluster is inducible by CHCA and that it consists of two transcriptional units, chcC1XTC2B1B2R and chcAaAbAc. Overexpression of the various genes in Escherichia coli, and purification of the recombinant proteins led to the functional characterization of ChcAaAbAc as subunits of a cytochrome P450 system responsible for CHCA hydroxylation; ChcB1 and ChcB2 as trans-4-hydroxyCHCA and cis-4-hydroxyCHCA dehydrogenases, respectively; ChcC1 was identified as a 4-oxoCHCA desaturase containing a covalently bound FAD; and ChcC2 was identified as a 4-oxocyclohexenecarboxylate desaturase. The binding constant of ChcAa for CHCA was found to be 0.37 mM. Kinetic parameters established for ChcB1 indicated that it has a high catalytic efficiency towards 4-oxoCHCA compared to trans- or cis-4-hydroxyCHCA. The Km and Kcat values of ChcC1 for 4-oxoCHCA were 0.39 mM and 44 s−1, respectively. Taken together with previous work on the identification of a pobA gene encoding a 4-hydroxybenzoate hydroxylase, we have now localized the remaining set of genes for the final degradation of protocatechuate before entry into the tricarboxylic acid cycle.

Objective: Recent advances in high-precision mammography and ultrasound screening have led to an increase in the detection of early lesions (ductal carcinoma in situ and small cancers) appearing as microcalcified lesions or microcystic images, and there needs to be an improvement in the accuracy of breast fine-needle aspiration biopsy (FNAB) assessing these lesions. The objective of this study was to investigate whether fractal analysis of Kirsch edge images for the tissue fragment inner structure (FKT) is useful in breast FNAB. FKT measures tissue fragment chromasia of hyperchromatic crowded tissue fragments (HCG), tissue fragment shape unevenness, and tissue fragment inner structure complexity. Study Design Materials: Nineteen epithelial tissue fragments of fibroadenoma (FA) from 7 patients and 52 tissue fragments of invasive breast carcinoma of no special type (IBC-NST) (grade 1–2) from 11 patients were assessed. First, tissue fragments were classified into small (smaller than 60 × 102 μm2), medium, and large (100 × 102 μm2 or larger), and the appearance rate of each size was determined. Second, for FKT, the luminance value of tissue fragment chromasia, the unevenness and fractal value, and the tissue fragment inner structure complexity were determined. In statistical analysis, the Steel-Dwass test, nonlinear discriminant analysis, and receiver operating characteristic analysis were performed, setting the significance level at p < 0.05. Results: “Unevenness of the tissue fragment shape,” “fractal value of the tissue fragment shape,” and “fractal value of the tissue fragment inner structure” were significantly higher in small and large tissue fragments in IBC-NST compared with those in FA. The specificity and sensitivity were the highest (100%) in small tissue fragments in multivariate analysis using 4 variables (“luminance value of tissue fragment chromasia,” “unevenness of tissue fragment shape,” “fractal value of the tissue fragment shape,” and “fractal value of the tissue fragment inner structure”). Conclusion: FKT, which evaluates “tissue fragment darkness,” “tissue fragment shape unevenness,” and “tissue fragment inner structure complexity” focusing on small tissue fragments of HCG in breast FNAB, is useful as a system that assists cytopathological assessment of breast FNAB.

The fungus Exophiala jeanselmei strain KUFI-6N produces a unique cycloalkanone monooxygenase (ExCAMO) that displays an uncommon substrate spectrum of Baeyer–Villiger oxidation of 4-10-membered ring ketones. In this study, we aimed to identify and sequence the gene encoding ExCAMO from KUFI-6N and overexpress the gene in Escherichia coli. We found that the primary structure of ExCAMO is most closely related to the cycloalkanone monooxygenase from Cylindrocarpon radicicola ATCC 11011, with 54.2% amino acid identity. ExCAMO was functionally expressed in E. coli and its substrate spectrum and kinetic parameters were investigated. Substrate profiling indicated that ExCAMO is unusual among known Baeyer–Villiger monooxygenases owing to its ability to accept a variety of substrates, including C4-C12 membered ring ketones. ExCAMO has high affinity and catalytic efficiency toward cycloalkanones, the highest being toward cyclohexanone. Five other genes encoding Baeyer–Villiger monooxygenases were also cloned and expressed in E. coli.

Background As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G). Patients and methods Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians’ discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors. Results Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant. Conclusions FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC., Highlights • This study compared febrile neutropenia (FN) incidences of 3 breast cancer regimens. • FN incidences were >20% in the 3 regimens (FEC, E(A)C; TC); TC showed the highest. • The relative dose intensities in visiting and non-visiting groups were at high level. • Age and pretreatment absolute neutrophil count were found as significant FN factors.

Background: Patients (pts) with HER2-positive locallyadvanced/metastatic breast cancer (LA/MBC) previously treated with pertuzumab(P)-containing regimens have few therapeutic options. The efficacy of Pre-treatment combined with trastuzumab (T)+chemotherapy as 3 or 4 -line chemotherapy was examined in such pts. Methods: Pts previously treated with P-containing regimens as1st/2nd-line treatment for LA/MBC were randomly assigned 1:1 to two groups(P+T+chemotherapy based on physicians’ choice (C) (PTC), and T+C (TC)),stratified by estrogen receptor status, previous P treatment duration, numberof previous chemotherapy regimens, and presence or absence of visceralmetastasis. The primary endpoint was investigator-assessed progression-freesurvival (PFS). Superiority of PTC to TC will be tested using a stratifiedlog-rank test that accounts for all stratification factors, and a one-sidedP-value of less than 0.05 will be considered an indicator of superiority. Thedistribution of PFS will be estimated using the Kaplan-Meier method. In addition,the hazard ratio and one-sided 95% CI of the therapeutic effect between thegroups will be calculated using the Cox proportional hazard model. Secondaryendpoints included independent reviewer assessed PFS, PFS in pts treated withT-DM1 as the latest regimen (PFS after T-DM1), objective response rate (ORR),overall survival (OS), safety, and health-related quality of life (HR-QoL). Results: Of the 219 pts enrolled, 217 (108 PTC, 109 TC) wereincluded in the intent-to-treat analysis. At the data cutoff (July 31, 2019),PFS and OS events were 184 (84.8%) and 84 (38.7%), respectively. Medianfollow-up time was 14.2 months (mo). Investigator-assessed PFS wassignificantly better in the PTC group (median PFS 5.3 vs. 4.2 mo; HR = 0.755[One-sided 95%CI upper limit, 0.967]; One-sided stratified log-rank test p =0.0217). Median PFS after T-DM1 (5.3 vs. 4.2 mo; HR = 0.801 [One-sided 95%CIupper limit, 1.061]; One-sided log-rank test p = 0.0952) and OS (28.8 vs. 23.4mo; HR = 0.713, [One-sided 95%CI upper limit, 1.026], One-sided log-rank test p= 0.062) tended to be longer in the PTC group, though further follow-up isneeded. The ORR with measurable disease (PTC (n = 90) 18.9% vs. TC (n = 92)19.6%) did not differ between the groups. The serious adverse event rate didnot differ between the groups (17.9% vs. 21.3%). There were no new safetysignals included cardiac events in the groups. In the comparison of HR-QoL bytime to deterioration analysis, there was no significant difference between thegroups in FACT-B trial outcome index (PTC 2.8 mo vs. TC 4.3 mo; HR = 1.274,log-rank test p = 0.2289).Conclusions: P re-treatment as 3 or 4 -line chemotherapy wasactive and feasible. P re-treatment can be a standard treatment option forpatients with HER2-positive LA/MBC previously treated with P.(ClinicalTrials.gov number: NCT02514681) Citation Format: Yutaka Yamamoto, Hiroji Iwata, Taira Naruto, Norikazu Masuda, Masato Takahashi, Tetsuhiro Yoshinami, Takayuki Ueno, Tatsuya Toyama, Takashi Yamanaka, Toshimi Takano, Masahiro Kashiwaba, Koichiro Tsugawa, Yoshie Hasegawa, Kenji Tamura, Hiroshi Tada, Fumikata Hara, Shigehira Saji, Satoshi Morita, Masakazu Toi, Shinji Ohno, Japan Breast Cancer Research Group. A randomized, open-label, phase III trial of pertuzumab re-treatment in HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab, and chemotherapy: The Japan Breast Cancer Research Group-M05 (PRECIOUS) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-11.

Background Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin–bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX. Methods We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was 1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded. Results One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42–1.28) in MD220 vs SD260, 0.77 (95% CI 0.47–1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56–1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180. Conclusions Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC., Highlights • Nab-Paclitaxel at 260 mg/m2 is used to treat metastatic breast cancer (MBC). • Nab-Paclitaxel frequently causes severe neuropathy or myalgia. • A reduced nab-paclitaxel dose of 180 mg/m2 q3w was effective and had less toxicities. • Therapeutic indices of reduced doses were increased compared to the standard dose.

To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m2 vs. MD: 220 mg/m2 vs. LD 180 mg/m2). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM). A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P

Improved prognosis for triple-negative breast cancer (TNBC) has plateaued and the development of novel therapeutic strategies is required. This study aimed to explore the anti-tumor effect of combined eribulin and HDAC inhibitor (vorinostat: VOR, pan-HDAC inhibitor and ricolinostat: RICO, selective HDAC6 inhibitor) treatment for TNBC. The effect of eribulin in combination with an HDAC inhibitor was tested in three TNBC cell lines (MDA-MB-231, Hs578T, and MDA-MB-157) and their eribulin-resistant derivatives. The expression of acetylated α-tubulin was analyzed by Western blotting for TNBC cells and immunohistochemical analyses for clinical specimens obtained from breast cancer patients who were treated with eribulin. The simultaneous administration of low concentrations (0.2 μM) of VOR or RICO enhanced the anti-tumor effect of eribulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. Meanwhile, pretreatment with 5 μM of VOR or RICO enhanced eribulin sensitivity in all three cell lines. Low concentration of VOR or RICO increased acetylated α-tubulin expression in MDA-MB-231 and Hs578T cells. In contrast, whereas 5 μM of VOR or RICO increased the expression of acetylated α-tubulin in MDA-MB-157 cells, low concentrations did not. Eribulin increased the expression of acetylated α-tubulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. These phenomena were also observed in eribulin-resistant cells. Immunohistochemical analyses revealed that the expression of acetylated α-tubulin was increased after eribulin treatment in TNBC. HDAC6 inhibition enhances the anti-tumor effect of eribulin through the acetylation of α-tubulin. This combination therapy could represent a novel therapeutic strategy for TNBC.

Objective: Because of the increased precision of ultrasound breast cancer screening, early cancer cases with no clear mass or extraction of microcysts on imaging have recently increased, and improvement of the accuracy of breast fine-needle aspiration biopsy (FNAB) cytology is needed. The objective of this study was to investigate the usefulness of cluster gray image-fractal analysis evaluating the darkness of clusters, cluster unevenness, and complexity of hyperchromicity (cluster density) of deep-stained cell clusters, known as hyperchromatic crowded cell groups (HCG), on FNAB as a cytology assistance system for breast FNAB. Study Design: One hundred clusters collected from 10 patients with fibroadenoma (FA), 90 clusters from 9 patients with ductal carcinoma in situ (DCIS), and 122 clusters from 11 patients with invasive breast carcinoma of no special type (IBC-NST) were used. (1) Cluster size classification: clusters were classified into small, middle, and large clusters (small cluster: smaller than 40 × 102 μm2; large cluster: 100 × 102 μm2 or larger; middle cluster: intermediate), and their frequency was calculated. (2) Cluster gray image-fractal analysis: (a) the darkness of clusters (luminance), (b) cluster unevenness (complexity), and (c) complexity of cluster density (roundness-corrected fractal value) were assessed. For statistical analysis, the multiple comparison Steel-Dwass test was used, with a significance level of p < 0.05. Results: (1) Cluster size classification: in FA, small, middle, and large clusters appeared at a similar frequency, and the frequency (30%) of large clusters was significantly higher than that in other diseases. In IBC-NST, many small clusters (61%) appeared and their frequency was significantly higher than that in other diseases, whereas the frequency of large clusters was significantly lower. (2) Cluster gray image-fractal analysis: in IBC-NST, the luminance of small clusters was low (dark), the cluster unevenness was high, and the complexity of cluster density was high, whereas the luminance of large clusters was high (bright), the cluster unevenness was high, and complexity of cluster density was high compared with those in FA. Conclusion: Cluster gray image-fractal analysis evaluating the darkness of clusters, cluster unevenness, and complexity of cluster density in breast FNAB HCG is a useful cytology assistance system for breast FNA.

SummaryPurpose To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast cancer (AMBC), this multicenter, open-label, phase II trial (JBCRG-M03: UMIN000012232) presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab. Methods We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013–April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and trastuzumabplus pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety. Results Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients [95% confidence interval (CI): 7.0–11.4]. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed. Conclusions In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC. Trial registration ID: UMIN-CTR: UMIN000012232.

Background: Febrile neutropenia (FN) is one of the greatest concerns when maintaining chemotherapy dosage for early breast cancer patients. However, the incidence proportion of FN remains unclear because of the empirical prescription of oral antibiotics, the use of G-CSF, and the absence of body temperature examination and hematology test. Therefore, we performed a prospective cohort study of FN in breast cancer patients receiving adjuvant or neoadjuvant chemotherapy. Methods: Breast cancer patients were prospectively enrolled from August 2015 to July 2017. The regimens included 4 cycles of FEC (epirubicin 100 mg/m²), E(A)C (epirubicin 90 mg/m² or doxorubicin 60 mg/m²), and TC (docetaxel 75 mg/m²). Considering the current practice of empirically prescribing oral antibiotics without hematology tests, we followed 2 groups and surveyed FN using 2 different definitions: true FN (T-FN): ≥ 37.5°C and grade 4 neutropenia by a hematologic test with a visit to the hospital (visiting group), and surrogate FN (S-FN): ≥ 37.5°C and oral antibiotic intake without a mandatory visit to the hospital (non-visiting group). The primary objective was to investigate the FN incidence of each regimen during the first 4 cycles. The overall incidence proportion of FN was calculated as (patients with T-FN or S-FN) / (total patients). The proportion of T-FN or S-FN in each group was also examined. In the secondary analysis, the risk factors of FN and the safety of FN management in the non-visiting group were investigated. Multiple logistic regression analysis was performed to assess the risk factors. As we assumed that FN occurs in 20% of the patients by these regimens, the planned sample size based on the confidence intervals was 1000. This trial was registered as UMIN 000017857. Results: A total of 1005 female patients with Stage I to III breast cancer were enrolled. Of these patients, 25 were excluded because of incomplete treatments or other regimens administered. There were 477 patients in the visiting group and 503 patients in the non-visiting group. The numbers of patients in each regimen were 338 in FEC, 335 in E(A)C, and 307 in TC. The overall incidence proportions of FN were 22.5%, 27.5%, and 33.9% in FEC, E(A)C, and TC, respectively. The incidence proportions of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5%. Pegfilgrastim (PEG-G) was used in the 1st cycle more frequently in the non-visiting group than in the visiting group: in FEC, E(A)C, and TC, 39.0%, 11.8%, and 52.1% in the non-visiting group; 4.71%, 1.82%, and 14.1% in the visiting group, respectively. The risk factors of FN were regimen (TC: OR: 2.67, 95%CI: 1.36-5.26), age (> 65 OR: 2.24, 95%CI: 1.34-3.75), neutrophil count at registration (/1000/μl: OR: 0.8, 95%CI: 0.67-0.95), pre-/post-operation (pre-: OR: 0.51, 95%CI: 0.29-0.88), and PEG-G (OR: 0.04, 95%CI: 0.01-0.34). There were no significant differences in the frequency of grade 3 adverse events, hospitalization, intake of oral antibiotics, and relative dose intensity between the visiting group and the non-visiting group. Therapeutic daily G-CSF was more frequently used in the visiting group than in the non-visiting group. Conclusions: FN occurred at a rate higher than 20% in these 3 regimens, most frequently in TC. Neutrophil count at registration was found to be one of the risk factors of FN. The current practice of prescribing antibiotics without hematologic tests is acceptable for FN management because the outcomes were not significantly different between the visiting group and the non-visiting group. Citation Format: Takashi Ishikawa, Kentaro Sakamaki, Kazutaka Narui, Hideki Nishimura, Takafumi Sangai, Kentaro Tamaki, Yoshie Hasegawa, Ken-ichi Watanabe, Nobuyasu Suganuma, Shintaro Michishita, Sadatoshi Sugae, Tomohiko Aiharya, Koichiro Tsugawa, Hiroshi Kaise, Hirofumi Mukai. Prospective cohort study of febrile neutropenia in breast cancer patients with neoadjuvant and adjuvant chemotherapy: CSPOR-BC FN Study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-09.

OBJECTIVE: Nab-paclitaxel (nab-PTX) has superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), but chemotherapy-induced peripheral neuropathy (CIPN) is more frequent with nab-PTX. In a single arm phase 2 trial (CA002-0LD), low dose nab-PTX (175 mg/m2) every 3 weeks (q3w) resulted in a good objective response rate (39.5%) without CIPN of grade 3 or higher. Therefore, we conducted a randomized controlled study to evaluate the optimal dose of nab-PTX by comparing a low dose (LD) and a medium dose (MD) to the standard dose (SD). Here, we evaluate the patients-reported outcomes (PROs) and health-related quality of life (HRQoL) in the ABROAD study. PATIENTS AND METHODS: Three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) were administered in patients with HER2-negative metastatic breast cancer. The primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates with the three doses were estimated by logistic regression. The optimal dose was selected by 2-step selection. First, if the hazard ratio (HR) for PFS was 1.33, the inferior dose was dropped. Then, a dose with an estimated incidence of grade 3/4 neurotoxicity >10% was also dropped. PROs and HRQoL were assessed as secondary endpoints at baseline, and during the 2nd, 4th and 6th courses of protocol treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Patient Neurotoxicity Questionnaire (PNQ), Cancer Fatigue Scale (CFS) and EuroQol 5 Dimension (EQ-5D). The primary outcome for PROs and HRQoL was the FACT-Taxane trial outcome index (TOI), and inter-group comparison was performed using a mixed effect model for repeated measures (MMRM). This trial was registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). RESULTS: A total of 141 patients were randomly assigned to SD (n=47), MD (n=46) or LD (n=48) nab-PTX. PFS analysis showed that LD nab-PTX at 180 mg/m2/3 weeks was the optimal dose with good clinical efficacy and tolerability for patients with MBC (reported by Hara at ASCO2019). Longitudinal analysis (MMRM) showed that the difference from the baseline FACT-Taxane TOI score at MD and LD were significantly better than that at SD (MD vs. SD p CONCLUSION: Our results show that low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose for PFS and from the perspectives of PROs and HRQoL. Citation Format: Hiroaki Kato, Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro Kikawa Yuichiro Kikawa, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Junji Tsurutani, Naruto Taira, Tsutomu Takashima, Kosuke Kashiwabara, Tomohiko Aihara Tomohiko Aihara, Hirofumi Mukai. Patient-reported outcomes in a randomized, optimal dose finding, phase II study of triweekly nab-paclitaxel in patients with metastatic breast cancer (the ABROAD study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-04.

Background: Eribulin mesylate (ERI) improved the overall survival in metastatic breast cancer (BC) patients. However, the efficacy has not been reported in early breast cancer. We performed the neoadjuvant chemotherapy (NAC) study based on hypothesis that ERI is less toxic, particularly in peripheral neuropathy, and has similar efficacy to paclitaxel (PTX) in patients with operable BC. Methods: This is a multicenter open label randomized phase 2 study (UMIN000012817). Patients were randomly assigned to either ERI (1.4mg/m2, d1 and d8, q21 days, 4 cycles) followed by FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) (ERI-FEC) or PTX (80mg/m2, weekly, 12 cycles) followed by FEC (PTX-FEC) with stratified by ER, HER2, and menopausal status. Trastuzumab was added in patients with HER2 positive disease. Primary endpoint was the incidence of peripheral sensory and motor neuropathy (PSN and PMN) with Grade 1 or higher according to CTCAE ver.4.0. Secondary endpoints were pathological complete response (pCR) rates (ypT0/is/ypN0), clinical response rates (CR+PR), adverse events, disease-free survival (DFS) and patient neurotoxicity questionnaire (PNQ) analysis. Here, we report 3 year’s DFS and PNQ analysis in this study Results: Between December 2013 to March 2016, 121 cases were enrolled and 5 cases were excluded from the primary assessment. One hundred sixteen cases were finally randomized and treated by ERI-FEC in 58 cases and PTX-FEC in 57 cases. A median follow-up time of ERI-FEC and PTX-FEC was 54.2 and 51.4 months, respectively. Three year-DFS rate were 89.7% in the ERI-FEC group (95% CI 51.1 - 57.3) and 86.0% in the PTX-FEC group. (p=0.561). The incidences of PSN and PMN were significantly lower in the ERI-FEC group than the PAX-FEC group at the end of treatments (previously reported). PNQ analysis after treatments is now undergone. Conclusion: DFS was not different between them. Although the pCR rate was lower in ERI-FEC than PAC-FEC as reported at the previous meeting. ERI was more favorable on adverse events than PTX during NAC treatments. Long-term results on neurotoxicity of these two drugs will be presented at the meeting. Citation Format: Takahiko Kawate, Takashi Ishikawa, Daishu Miura, Yoshie Hasegawa, Akihiko Tachibana, Jun Horiguchi, Mitsuhiro Hayashi, Masaru Miyashita, Tomoyuki Kubota, Kazutaka Narui, Masato Suzuki, Kouhei Akazawa, Norio Kohno. Randomized controlled trial of neoadjuvant eribulin mesylate versus paclitaxel in women with operable breast cancer (JONIE-3 study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-07.

Background: There are now many treatment options for estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, there are few reports indicating the optimal treatment sequence for this disease. Information to predict response to treatment is vital for personalized therapy and determining the most beneficial approach for individual patients. In this study, we attempted to determine predictive factors of response to hormonal therapy and survival outcomes using the large-scale databases constructed in the Safari study (UMIN000015168), a retrospective, multicenter cohort study involving 1,072 Japanese patients receiving fulvestrant 500mg for ER+ ABC. We examined the association between clinicopathological factors and time to failure (TTF) of fulvestrant in Japanese ABC patients. Methods: Among 1072 patients, 247 patients were selected for this study. Inclusion criteria was as follows: 1) patients treated with either SERM or AI in the adjuvant setting (AS) with known starting and finishing date of the treatment (patients relapsed on adjuvant treatment were excluded), 2) patients treated with SERM, AI and SERD in the metastatic setting (MS) as the first and the second line treatment. Influence of the adjuvant hormonal therapy on the TTF of the first line and the second line treatment and overall survival (OS) was assessed. Cox proportional hazards model was used for this analysis. Results: Patients treated with SERM in AS had significantly longer TTF of 1st line and 1st+2nd line of hormonal therapy in MS (1st line: HR 1.519, 95% CI 1.04-2.218, p=0.0307, 1st+2nd line: HR 2.372, 95% CI 1.584-3.551, p Conclusions: Interestingly, once AI-treated patients in AS have relapsed, their hormone sensitivity is lower and survival outcomes are worse compared with SERM-treated patients in AS in this cohort. Our results have consistency with the results of ABCSG-12 trial showing a pronounced higher risk of death for anastrozole-treated patients (Annals of Oncology 26: 313–320, 2015). Since it is a cohort of selected patients who were successfully treated with fulvestrant, prospective analysis would be therefore warranted. Citation Format: Takahiro Nakayama, Hidetoshi Kawaguchi, Norikazu Masuda, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Influence of the adjuvant hormonal therapy on hormone sensitivity and survival outcomes in ER+ and HER2−advanced breast cancer: A subgroup analysis of the JBCRG-C06 Safari study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-11.

Background: The standard chemotherapy treatment strategy for patients with advanced/metastatic breast cancer (ABC) is the continuation of the same drug until tumor progression. However, despite continued antitumor effects, continuation of a drug often becomes difficult because of cumulative adverse events, such as peripheral neuropathy. Methods: This multicenter, randomized, Phase II study in patients with estrogen receptorpositive (ER+) human epidermal growth factor receptor 2-negative (HER2−) ABC aimed to compare 2 treatment strategies following induction therapy with 4-6 cycles of the combined use of weekly paclitaxel (wPTX) and bevacizumab (BV). Patients in Arm A continued with wPTX+BV, whereas patients in Arm B were switched from wPTX to maintenance endocrine therapy (endocrine+BV) until disease progression, followed by wPTX+BV re-induction. The primary endpoint was time to failure of strategy (TFS), defined as the time from randomization to a qualifying event (addition of a new agent not in the primary regimen, progressive disease during or after planned therapy, or death). Secondary endpoints were overall survival (OS), progression-free survival, safety, and quality of life (QoL). Sequential plasma and serum biomarkers were analyzed for predicting/monitoring the response. Result: Of 160 patients enrolled to receive induction therapy with wPTX+BV, 125 patients responded to treatment (complete response [CR], partial response [PR], or stable disease) and were randomized to either of the 2 treatment arms. Median follow-up was 21.3 months. Aromatase inhibitor (AI), fulvestrant, or AI with a luteinizing hormonereleasing hormone (LH-RH) analogue was used as maintenance endocrine therapy. The primary endpoint of TFS was 8.87 months (95% CI: 5.68-13.80) in the wPTX+BV continued group (Arm A) and 16.82 months (95% CI: 12.88-18.99) in the maintenance endocrine+BV group (Arm B) (hazard ratio [HR], 0.51; p Conclusion: This is the first study showing the benefit of maintenance endocrine therapy in patients with ER+ HER2− advanced breast cancer who responded to a fixed dose of chemotherapy. (UMIN: UMIN000012179; ClinicalTrials.gov: NCT01989780) Funding: Chugai Pharmaceutical CO., LTD. Citation Format: Shigehira Saji, Masahiro Kitada, Toshimi Takano, Masahiro Takada, Tohru Ohtake, Tatsuya Toyama, Yuichiro Kikawa, Yoshie Hasegawa, Tomomi Fujisawa, Masahiro Kashiwaba, Takanori Ishida, Rikiya Nakamura, Yutaka Yamamoto, Uhi Toh, Hiroji Iwata, Norikazu Masuda, Naruto Taira, Satoshi Morita, Shinji Ohno, Masakazu Toi. A randomized, multicenter, phase II study evaluating the efficacy of interventional maintenance endocrine therapy with bevacizumab following fixed cycles of bevacizumab plus paclitaxel in advanced/metastatic ER-positive HER2-negative breast cancer: JBCRG-M04 BOOSTER trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-01.

Background: After the CONFIRM trial, fulvestrant 500 mg (F500) became a standard treatment for patients with estrogen receptor positive (ER+) advanced/metastatic breast cancer (AMBC). The JBCRG-C06 Safari study (UMIN 000015168) showed that earlier F500 use, a longer time from diagnosis to F500 use, and no prior chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with ER+ and HER2-negative AMBC (Kawaguchi H, et al. Breast Cancer Res Treat, 2017; Kawaguchi H, et al. Curr Med Res Opin, 2018). We had carried out subgroup analyses on real world data from the Safari study focusing on ER+ and HER2+ AMBC with the objective to examine further on potential interactions between TTF and the following: F500 single treatment or F500 with anti-HER2 therapy; presence or absence of visceral metastasis; progesterone receptor (PgR) status; and prior chemotherapy for AMBC. Material & methods: The Safari study was a retrospective, multicenter cohort study, conducted in 1072 patients at 16 sites in Japan for ER+ AMBC. Patients starting treatment with F500 between Nov 2011 and Dec 2014 were registered. After the data cleaning through the central review, 94 patients (9.6%) has been included in this sub-analysis among the 978 patients in which HER2 status was confirmed by the documentation. The relationship between baseline clinical/pathological factors, treatment line, and TTF (time from start to cessation of F500 treatment for any reason, including toxicity and death) were analyzed using Kaplan-Meier methods. Univariate analysis of TTF data was performed by Cox hazards model using: age, histological type, histological/nuclear grade, visceral-metastases, stage, PgR, period from AMBC diagnosis to F500 use, treatment line of F500, prior chemotherapy. Results: Median age at diagnosis of AMBC was 57.5yrs (33-85); 59(33-85) and 56.5(39-75) for F500 with/ without anti-HER2 therapy. Median age of fulvestrant start was 61yrs (35-96). 21.3% had de novo metastatic disease; 78.7% recurrent disease; 37.2% visceral metastases. All patients’ ER status was positive, and PgR status was positive in 65.9%, negative 25.5% respectively. HER2 IHC 3+ patients accounted for 44.7%, IHC 2+/1+ for 38.3%. In the case of IHC 2+/1+, HER2-positivity was confirmed by FISH. F500 alone was administered in 52 patients, while F500 with anti-HER2 therapy in 42 patients. At median follow up of 3.9 years, median TTF was 4.4m (95% CI: 3.3-5.7); 3.7m (95% CI: 2.9-5.9), 5.1m(95% CI: 3.6-6.4) for the F500 alone group, F500 with anti-HER2 therapy group respectively (p = 0.5973). F500 with/ without anti-HER2 therapy was administered in 1stor 2nd-line in 20 (21.3%), and ≥3rd-line in 74(78.7%) patients. Median TTF was 6.6m (95% CI: 4.6-8.5) and 3.7m (95% CI: 2.8-5.2) in the 1stor 2nd-line and ≥3rd-line respectively (p value:0.0145). Although no statistically significant difference was found, TTF tended to be shorter in the group receiving chemotherapy prior to F500 (median TTF: 3.7m vs 5.5m). No other clinical parameters including age, PgR status, metastatic sites were associated with the effectiveness. The median OS was 7.8-years (95% CI: 5.9-9.5), which had not been influenced by with/ without anti-HER2 therapy. The toxicity profile we observed was similar to that in the registration trial. Conclusions: Our findings suggest that F500 with/without anti-HER2 therapy appears to be effective also in the ER+ and HER2-positive ABMC setting which is consistent with the limited results previously published. Earlier line use of F500 use may be useful in HER2-positive patients as well as HER2-negative patients. Citation Format: Misato Hagi, Hidetoshi Kawaguchi, Norikazu Masuda, Shigehira Saji, Yutaka Yamamoto, Takahiro Nakayama, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Daisuke Yotsumoto, Satoshi Morita, Masakazu Toi, Shinji Ohno. Outcomes of fulvestrant therapy among Japanese women with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of the JBCRG-C06 safari study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-13.

Background: To evaluate the survival risk is an important factor to decide or treatment options for recurrent breast cancer patients with estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2−), though there are not enough supporting reports from large-scale databases. The Safari study (UMIN000015168) is a newly conducted retrospective, multicenter cohort study including 1072 ER+ advanced breast cancer Japanese patients treated with fulvestrant 500 mg mostly as a second or later line hormonal therapy. The follow-up data of Safari study is evaluated to focus on any relationship between clinicopathological factors and post-recurrence survival (PRS) in ER+ HER2− recurrent breast cancer patients. Methods: PRS was defined as the duration from the date of initial treatment for recurrent breast cancer to death. The Cox hazards model was used to evaluate the relationship between the clinical factors and PRS. We also performed multivariate analysis on PRS using factors that showed a statistical difference (p < 0.15) in univariate analysis. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p-values are described. All tests were two-sided and p Citation Format: Kenjiro Aogi, Hidetoshi Kawaguchi, Norikazu Masuda, Takahiro Nakayama, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Factors associated with prolonged post-recurrence survival in patients with postmenopausal estrogen receptor-positive breast cancer taking fulvestrant: A follow-up data of the JBCRG-C06 Safari study factors associated with prolonged post-recurrence survival in patients with postmenopausal estrogen receptor-positive breast cancer taking fulvestrant: A follow-up data of the JBCRG-C06 Safari study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-55.

The degradation pathways in microorganisms for piperidine, a secondary amine with various applications, are not yet fully understood, especially in non-Mycobacterium species. In this study, we have identified a piperidine-degrading isolate (KU43P) from a soil sample collected in a cultivation field in Osaka, Japan, and characterized its mechanisms of piperidine degradation, thereby furthering current understanding of the process. The genome of isolate KU43P consists of a 5,869,691-bp circular chromosome with 62.67% GC content and with 5,294 predicted protein-coding genes, 77 tRNA genes, and 22 rRNA genes. 16S rRNA gene sequence analysis and average nucleotide identity analysis suggest that the isolate is a novel species of the Pseudomonas putida group in the genus Pseudomonas. The genomic region encoding the piperidine degradation pathway, designated as the pip gene cluster, was identified using transposon mutagenesis and reverse transcription polymerase chain reaction. Deletion analyses of pipA, which encodes a glutamine synthetase (GS)-like protein, and pipBa, which encodes a cytochrome P450 monooxygenase, indicate that pipA and pipBa are involved in piperidine metabolism and suggest that pipA is involved in the first step of the piperidine metabolic pathway. Escherichia coli whole cells overexpressing PipA converted piperidine and glutamate to γ-glutamylpiperidide, and crude cell extract enzyme assays of PipA showed that this reaction requires ATP and Mg2+. These results clearly show that pipA encodes γ-glutamylpiperidide synthetase and that piperidine is first glutamylated and then hydroxylated in the piperidine degradation pathway of Pseudomonas sp. strain KU43P. This study has filled a void in the general knowledge of the microbial degradation of amine compounds.

Background Assessing survival risk is important for discussing treatment options with estrogen receptor-positive (ER+) advanced breast cancer (ABC) patients. However, there are few reports from large-scale databases on the survival risk factors in ER+ ABC. The Safari study (UMIN000015168) was a retrospective, multicenter cohort study involving 1072 Japanese patients receiving fulvestrant 500 mg mostly as a second- or later-line endocrine therapy for ER+ ABC. The follow-up data after the Safari study were examined, focusing on any relationship between clinicopathological factors and overall survival (OS) in ER+ ABC patients. Methods OS in patients with ER+ ABC was analyzed by univariate and multivariate analyses with a Cox proportional hazards model in this study. Results A total of 1031 cases were evaluable for OS analysis. Multivariate analysis showed that younger age ( Conclusions In ER+ ABC patients whose treatment history included fulvestrant, younger age, longer time from ABC diagnosis to fulvestrant use, no prior palliative chemotherapy use, PgR−, and lower histological or nuclear grade correlated positively with prolonged OS.

BACKGROUND/AIM Risk factors for chemotherapy-induced nausea and vomiting (CINV) with anthracycline-containing regimen for breast cancer patients remain unknown. The risk factors for CINV with FEC100 were investigated. PATIENTS AND METHODS Data on CINV events and patient backgrounds of 180 patients were collected from the first cycle of FEC100 treatment. In this regimen, patients were administered various antiemetics (ADs). The combinations of ADs were classified into four categories, while body mass index (BMI) was stratified into three categories. Risk factors were selected based on patient characteristics and combination of ADs. Risks for CINV were analyzed by univariate and multivariate analyses. RESULTS In the univariate analysis of nausea, BMI was a significant factor, while BMI and combination of ADs were significant in vomiting. In the multivariate analysis concerning nausea, BMI was a significant factor. In the analysis concerning vomiting, the combination of ADs and BMI were significant. CONCLUSION BMI was the most important risk factor for nausea and vomiting, while the combination of ADs was for vomiting.

Background The Safari study (UMIN 000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive (ER+) advanced breast cancer (ABC) treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival (OS) after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure (TTF) in patients with ER + ABC. The current study is an ad-hoc analysis that focused on the relationship between the patient factors and OS after recurrence by adding factors generally associated with OS after recurrence. Methods The OS after recurrence in patients with ER + human epidermal growth factor receptor 2 negative (HER2−) recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model. Results A total of 598 cases were used for the analysis of OS after recurrence. Multivariate analysis revealed that favorable OS (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥ 3 years), low nuclear or histological grade (G3 vs. G1), long TTF of initial palliative endocrine therapy (≥ 12 months), and long time to initial palliative chemotherapy (≥ 2 years). Conclusion In patients with ER + HER2 − recurrent breast cancer who received endocrine therapy as the primary palliative treatment, the low proliferation activity of the tumor at the first diagnosis, sensitivity to initial endocrine therapy after the recurrence, and long time to the initiation of chemotherapy might be correlated with the favorable OS after recurrence. Trial registration: University Hospital Medical Information Network: UMIN 000015168, 2014/09/16

Background: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on the risk of breast cancer recurrence. Methods: This prospective, randomised, multicentre open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients with stage I–IIIA hormone receptor-positive breast cancer who were disease-free after treatment with either 5 years of anastrozole alone or 2–3 years of tamoxifen followed by 2–3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole (1 mg/day orally) for an additional 5 years or stop anastrozole, using the central computer at the Comprehensive Support Project for Oncology Research Data Centre. Randomisation was stratified by type of postoperative endocrine therapy, nodal status, prior adjuvant chemotherapy, and facility. The primary endpoint was disease-free survival, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with UMIN clinical trials registry, number UMIN000000818. Findings: We enrolled 1697 patients from 117 facilities between November 2007 and November 2012. Patients were assigned randomly to the continue group (n=849) or the stop group (n=848). Follow-up information was available for 1593 patients (n=787 in the continue group, n=806 in the stop group) as the full analysis set. After a median follow-up of 5·1 years, there were 172 events involving disease recurrence or the occurrence of contralateral breast cancer (75 in the continue group and 97 in the stop group) and 40 deaths (21 in the continue group and 19 in the stop group). The 5-year disease-free survival rates were 91% (95% confidence interval [CI] 89–93) in the continue group and 86% (95% CI 83–88) in the stop group (hazard ratio [HR] for disease-free survival 0·61, 95% CI 0·46–0·82; p

BACKGROUND/AIM We evaluated the impact of the relative dose intensity (RDI) of neoadjuvant chemotherapy (NAC) on the survival of patients with breast cancer (BC). PATIENTS AND METHODS This randomized phase II trial included 188 patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with anthracycline followed by paclitaxel as NAC. We grouped patients using a relative dose intensity (RDI) threshold of 85% and evaluated clinicopathological features and clinical outcomes. RESULTS The 5-year overall survival rate was 91.2% and 76.3%, when RDI ≥85% and

Background Pathological complete response (pCR) is often achieved by neoadjuvant chemotherapy (NAC), particularly in hormone receptor-negative breast cancer. Contrast-enhanced magnetic resonance imaging (cMRI) is the most reliable imaging modality to evaluate the pathological effect of NAC. Ultrasonography is indispensable to collect representative specimens from the target lesion by core needle biopsy (CNB). This study aimed to evaluate the accuracy of predicting pCR by adding CNB after NAC, in cases with complete clinical response (cCR) diagnosed by cMRI. Methods In this prospective multicentre study, we evaluated patients diagnosed with cCR by cMRI after NAC. Ultrasound-guided CNB (uCNB) using a 14G needle was performed without clip markers under general anaesthesia as planned surgery. Specimens collected by uCNB were compared to those resected surgically and were categorized as (i) no carcinoma (ypT0), (ii) no invasive carcinoma and only residual carcinoma in situ (ypTis) and (iii) residual invasive carcinoma. The concordance of pathological results between the uCNB and surgical specimens was evaluated. Results Of the 83 patients evaluated, 41 (49.4%) and 17 (20.5%) of them had ypT0 and ypTis, respectively. The false negative rates (FNR), sensitivity and specificity for predicting ypT0 by uCNB were 50.0%, 50.0%, 100%, respectively, and those for predicting ypT0+ypTis were 28.0%, 72.0% and 98.3%, respectively. The concordance rates were 74.7% (62/83) for ypT0 and 90.4% (75/83) for ypT0+ypTis. Conclusion In cCR cases diagnosed by cMRI, uCNB was not accurate enough to predict pCR. Additional modalities like clip placements and/or thicker core needles may be required for better prediction.

Background This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. Methods Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated. Results Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events. Conclusion This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule. Clinical trial registration University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491). Electronic supplementary material The online version of this article (10.1007/s12282-018-0843-y) contains supplementary material, which is available to authorized users.

The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2-) cases.The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (n = 960). Of these, 828 patients were HER2-. Results Multivariate analysis showed that advanced age (≥65 years; p = .035), longer time (≥3 years) from ABC diagnosis to F500 use (p .001), no prior chemotherapy (p .001), and F500 treatment line (p .001) were correlated with prolonged TTF (median = 5.39 months).In ER+/HER2- patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen.” There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 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. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.

This retrospective study evaluated the effect of clinical background and treatment line on time to treatment failure (TTF) in advanced/metastatic breast cancer (AMBC) patients receiving F500 in Japan (UMIN 000015168). Patients who commenced F500 treatment were registered at 16 sites in Japan. Correlations between baseline clinicopathological factors, treatment line, and TTF were investigated by Kaplan–Meier analysis. TTF data were analyzed using univariate analysis and multivariate analysis with a Cox proportional hazards model. Data for 1072 patients were available; 1031 patients (96.2%) were evaluable for efficacy. F500 was administered as first-line treatment in 2.0%, second-line in 22.7%, third-line in 26.7%, and ≥fourth-line in 48.6% patients. Median TTF was 5.4 months. Multivariate analysis found that earlier F500 use (first and second vs. third vs. ≥fourth line; hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.74–0.86; P

Besides an industrial pollutant, 2,4-dinitrophenol (DNP) has been used illegally as a weight loss drug that had claimed human lives. Little is known about the metabolism of DNP, particularly among Gram-negative bacteria. In this study, two non-contiguous genetic loci ofParaburkholderia(formerlyBurkholderia) sp. strain KU-46 genome were identified and four key initial genes (dnpA,dnpB, anddnpC1C2) were characterized to provide molecular and biochemical evidence for the degradation of DNP via the formation of 4-nitrophenol (NP), a pathway that is unique among DNP utilizing bacteria. Reverse transcription PCR analysis indicated that thednpAgene encoding the initial hydride transferase (28 kDa), and thednpBgene encoding a nitrite-eliminating enzyme (33 kDa), are inducible by DNP and the two genes are organized in an operon. Purified DnpA and DnpB from overexpression clones inEscherichia colieffected the transformation of DNP to NP via the formation of hydride-Meisenheimer complex of DNP. The function of DnpB appears new since all homologs of DnpB sequences in the protein database are annotated as putative nitrate ABC transporter substrate-binding proteins. The gene cluster responsible for the degradation of DNP after NP formation was designateddnpC1C2DXFER.DnpC1 and DnpC2 were functionally characterized as the respective FAD reductase and oxygenase components of the two-component NP monooxygenase. Both NP and 4-nitrocatechol were shown to be substrates, producing hydroquinone and hydroxyquinol, respectively. Elucidation of thehqdA1A2BCDgene cluster allows the delineation of the final degradation pathway of hydroquinone to ß-ketoadipate prior to its entry to the tricarboxylic acid cycle.ImportanceThis study fills a gap in our knowledge and understanding of the genetic basis and biochemical pathway for the degradation of 2,4-dinitrophenol (DNP) in Gram-negative bacteria, represented by the prototypicalParaburkholderiasp. strain KU-46 that metabolizes DNP through the formation of 4-nitrophenol, a pathway unseen by other DNP utilizers. The newly cloned genes could serve as DNA probes in biomonitoring as well as finding application in new biocatalyst development to access green chemicals. By and large, knowledge of the diverse strategies used by microorganisms to degrade DNP will contribute to the development of bioremediation solutions since DNP is an industrial pollutant used widely in the chemical industry for the synthesis of pesticides, insecticides, sulfur dyes, wood preservatives, and explosives, etc. (119 words)

Background: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. Patients and methods: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I–IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1–L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were (1) rate of change in the lumbar spine (L1–L4) BMD after 2, 3, 4, and 5 years; (2) rate of change in the femoral neck BMD; (3) rate of change in radius BMD (determined using an ultrasonic bone densitometer); (4) changes in calcium and bone metabolism markers (TRAP 5b, bone alkaline phosphatase, and pentosidine); (5) development of pathological fracture within 3 years; (6) disease-free survival; (7) overall survival (OS); (8) adverse events; and (9) quality of life. Ethics and dissemination: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. Trial registration: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.

Background: Neoadjuvant chemotherapy (NAC) reduces tumor size, and increases the frequency of breast-conserving surgery in operable breast cancers. Response predictions to NAC are made based on diagnostic imaging. Although various studies have reported the optimal timing for diagnostic imaging, this still remains unclear. Purpose: To identify the optimal timing of diagnostic imaging for the response prediction to NAC, and to evaluate the accuracy of response prediction. Methods: We evaluated 146 cases enrolled in the JONIE-1 study (a randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a NAC in patients with HER2-negative primary breast cancer). The chemotherapy regimen was FEC100×4 courses followed by weekly paclitaxel 80×12 courses (± zoledronic acid). Statistical analysis of the association between the tumor reduction ratio and the histopathological response and the prediction of pathological complete response (pCR) was performed using JMP software. The maximum tumor diameter was evaluated using magnetic resonance imaging and ultrasound on each patient 3 times (before NAC, after FEC treatment, after NAC) and tumor reduction ratios were calculated. Results: The average age of the patients was 49.8 years old. The menopause status was pre-menopause in 84 patients, and post-menopause in 58 patients. Regarding the subtype classification, 116 patients were of the luminal type (Lum) and 26 patients were triple negative (TN), and the Ki-67 labeling index had a median of 25% (1%-93%). Pathological examination demonstrated that 16 patients had pCR(11.3%, Lum, 9;TN: 7), and 126 patients had non-pCR (88.7%, Lum:107; TN:19). Seven patients had clinical-CR (4.8%, Lum: 4; TN: 3) at post-FEC, and 26 patients (17.8%, Lum: 20; TN: 6) at post-NAC. The prediction of pCR at post-FEC and post-NAC was evaluated by single variable analysis, resulting in an AUC (0.75645) p=0.0017 at post-FEC, and AUC (0.76563) p=0.0001 at post-NAC. The sensitivity / specificity / positive predictive value / negative predictive value were 0.625 / 0.873 / 0.385 / 0.948 at post-FEC, 0.250 / 0.976 / 0.571 / 0.911 at post-NAC, respectively. In TN cases, the values were 0.714 / 0.947 / 0.833 / 0.900 in post-FEC, and 0.429 / 1.000 / 1.000 / 0.826 in post-NAC. Conclusions: Diagnostic imaging evaluation performed after FEC treatment was useful for the prediction of pCR. Furthermore, the reliability was high in Triple Negative Sub type, but is affected by the existence of residual tumors in Luminal type. Citation Format: Kaise H, Ishikawa T, Miura D, Hasegawa Y, Horiguchi J, Hayashi M, Takao S, Kim SJ, Tanino H, Miyashita M, Konishi M, Shigeoka Y, Yamagami K, Suzuki M, Taguchi T, Akazawa K, Kohno N. Early and accurate prediction of pathological response by magnetic resonance imaging and ultrasonography in patients undergoing neoadjuvant chemotherapy for operable 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 P3-07-50.

Purpose The Recurrence Score test is validated to predict benefit of adjuvant chemotherapy. TransNEOS, a translational study of New Primary Endocrine-therapy Origination Study (NEOS), evaluated whether Recurrence Score results can predict clinical response to neoadjuvant letrozole. Methods NEOS is a phase 3 clinical trial of hormonal therapy ± adjuvant chemotherapy for postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer, after six months of neoadjuvant letrozole and breast surgery. TransNEOS patients had tumors ≥ 2 cm and archived core-biopsy samples taken before neoadjuvant letrozole and subsequently sent for Recurrence Score testing. The primary endpoint was to evaluate clinical (complete or partial) response to neoadjuvant letrozole for RS

Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months. This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months. At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur. Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.

Background: The addition of bisphosphonates to adjuvant systemic therapy reduces bone metastases and improves survival in postmenopausal patients with early breast cancer. We have conducted four randomised trials of neoadjuvant chemotherapy (CT) +/- zoledronic (ZA) in stage II/III breast cancer to investigate the potential for enhancing pathological response within the breast and axilla. We report here a meta-analysis of these studies to enable more reliable evaluation of treatment effects and investigate activity in pre-defined subgroups of interest. Methods: Individual patient data from four prospective randomized clinical trials reporting the effect of the addition of ZA on pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (pCRb) and in the breast and lymph nodes (pCR). A fixed effects Mantel-Haenszel meta-analysis was performed using odds ratios (OR) from multivariate analyses in each study correcting for T-status and ER-status after testing for heterogeneity. Predefined subgroup analyses were performed for postmenopausal women and patients with triple-negative breast cancer. Results: pCRb and pCR data were available in 736 and 553 women respectively. A summary of results is shown in the table below. In the total study population, ZA addition to neoadjuvant CT did not increase pCRb/pCR rates (12.9% for CT only vs. 16.0% with CT+ ZA; OR 1.34, 95% C.I. 0.86-2.08). However, in postmenopausal women, the addition of ZA resulted in a doubling of the pCRb rate (8.5% for CT only vs. 17.0% with CT+ ZA; OR 2.72, 95% C.I. 1.15-6.42) and pCR rate (7.8% for CT only vs. 13.6% with CT+ ZA; OR 2.48, 95% C.I. 0.80-7.69). There was significant interaction between menopausal status and ZA benefit (P for interaction=0.047). In patients with triple-negative breast cancer a trend was observed favouring CT+ZA. Pathological responseCTCT + ZAOdd's Ratio95% C.I.pCRb/totalPercentagepCRb/totalPercentagepCR in breastTotal population48/37312.958/36316.01.340.86-2.08Postmenopausal patients11/1308.524/14117.02.721.15-6.42*Pre/perimenopausal patients34/23214.733/21415.41.030.59-1.79Triple-negative breast cancer13/7018.621/6731.31.990.85-4.66pCR/totalPercentagepCR/totalPercentagepCR in breast and lymph nodesTotal population28/27910.033/27412.01.310.73-2.34Postmenopausal patients7/907.814/10313.62.480.80-7.69Pre/perimenopausal patients19/17810.718/16311.01.000.49-2.08Triple-negative breast cancer9/5217.315/5129.41.800.63-5.21Overview of pCRb and pCR in both treatment arms in the total population and predefined subgroups Conclusion: This meta-analysis shows that no overall benefit from the addition of ZA to neoadjuvant CT. However, as has been seen in the adjuvant setting, the addition of ZA to CT in postmenopausal women with early breast cancer appears to specifically increase the effects of CT with increases in pCRb and pCR. Further translational research is warranted to explore the mechanism of these observations and the potential treatment interaction with menopause. Citation Format: Judith R Kroep, Ayoub Charehbili, Rob E Coleman, Rebecca L Aft, Yoshie Hasegawa, Gerrit-Jan Liefers, Matthew C Winter, Katherine N Weilbaecher, Kohei Akazawa, Samantha Hinsley, Hein Putter, Hans WR Nortier, Norio Kohno. Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-04.

Background: Whether adjuvant chemotherapy is required for patients with intermediate-risk endocrine-responsive postmenopausal breast cancer remains unknown. The New primary Endocrine-therapy Origination Study (NEOS: N-SAS BC06 study: UMIN 000001090 (http://www.umin.ac.jp/) was a randomized controlled trial to verify the necessity of adjuvant chemotherapy in node-, ER+, and HER2- postmenopausal breast cancer patients who responded to neoadjuvant endocrine therapy. The primary registration and primary treatment have finished. This report evaluated clinical responses and radiological findings in the neoadjuvant LET treatment phase of 6 months. Methods: Patients meeting eligibility criteria received LET preoperatively in weeks 24-28 after primary enrollment. Patients evaluated as complete response (CR), partial response (PR) or stable disease (SD) by each investigators underwent secondary enrollment and will be divided at random into two arms, an arm given LET for 4.5-5 years after chemotherapy and another arm given only LET for 4.5-5 years. Patients evaluated as progressive disease during LET treatment will receive discretionary treatment. The primary endpoint was disease-free survival and secondary endpoints were overall survival, clinical response rate in neoadjuvant treatment phase, pathological response, breast-conserving surgery rate, DFS/OS in subgroups according to clinical response, safety, HRQOL, and cost-effectiveness. Results: Between May 2008 and June 2013, 905 patients entered primary registration. We excluded 42 patients without confirmed data. The 863 included patients’ characteristics at baseline are: median age: 63 years old, median Body Mass Index (BMI):23.90, T1c:37%, T2:63%, and PgR+:79%, and 74% of patients had planned breast-conserving surgery (BCS). The clinical responses were evaluated with calipers, ultrasound and MRI (or CT) at the baseline and end of treatment before surgery. Clinical response rates were 2, 48, 46 and 4% in CR, PR, SD and PD, respectively. Excluding those who could not enter secondary registration according to the protocol, 83 (56.1%) of 148 patients with planned total mastectomy were converted to BCS according to final radiological evaluations before surgery. The correlation between the tumor size on MRI (r=0.87) after neoadjuvant LET and the pathological invasive tumor size was stronger than with other modalities (r=0.68, 0.57, 0.33 by CT, US and calipers, respectively). On univariate analysis, a small tumor size (T1c rather than T2), PgR+, HER2:2+ and a high BMI at the baseline were significantly correlated with the clinical response. On multivariate analysis, PgR + (HR: 1.13, 95%CI: 1.01-1.27, p=0.032) and a small tumor size (HR: 1.11, 95%CI: 1.03-1.17, p=0.003) were significant independent predictors of the clinical response. Conclusion: This is the first clinical report of neoadjuvant hormone therapy for early breast cancer. Neoadjuvant LET therapy improved BCS rates. MRI was useful for predicting the residual pathological invasive tumor size. PgR + and a small tumor size at the baseline were significant independent predictors of the clinical response. Citation Format: Takehiko Sakai, Hiroji Iwata, Yoshie Hasegawa, Rikiya Nakamura, Hiromitsu Akabane, Shoichiro Ohtani, Masahiro Kashiwaba, Naruto Taira, Tatsuya Toyama, Yutaka Yamamoto, Tomomi Fujisawa, Norikazu Masuda, Takuhiro Yamaguchi, Hirofumi Mukai, Yasuo Ohashi. First report of clinicopathological analysis in neoadjuvant treatment phase in NEOS: A randomized study of adjuvant endocrine therapy with or without chemotherapy for postmenopausal breast cancer patients who responded to neoadjuvant letrozole [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-14-01.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is very rare, with only 61 cases reported to date. EMPSGC is considered to be a low-grade carcinoma of sweat gland origin. Dermoscopic findings of EMPSGC have not been previously reported. We report the first case of a man with EMPSGC, featuring dermoscopic findings. Dermoscopic examinations of the present EMPSGC lesion revealed tumor cell proliferation that appeared as pink ovoid nests and elongated epidermis that resembled a whitish-pink network. Another characteristic finding of the present lesion was the large red/blue globules in pink ovoid nests in the tumor. Those reflected lacunae containing secretory fluid with red blood cells. We think that the large red/blue globules in pink ovoid nests in our case could be a characteristic dermoscopic finding specific to EMPSGC. We dermatologists encounter many "pink nodules" at out-patient clinics. The present dermoscopic findings may be useful for the differential diagnosis of EMPSGC.

Trials of adjuvant endocrine therapy for breast cancer have shown that aromatase inhibitors have little impact on global health-related quality of life (HRQoL), but have significant effects on patient-reported endocrine symptoms (ESs). There are few studies of HRQoL and psychological distress during preoperative endocrine therapy performed to determine endocrine responsiveness. The NEOS trial is a multicenter, phase 3 randomized controlled trial in postmenopausal women with hormone receptor-positive breast cancer. The primary aim of the trial was to evaluate the need for adjuvant chemotherapy in patients with clinical T1c-T2N0M0, hormone receptor-positive tumors who responded to neoadjuvant letrozole (LET) administered for 24-28 weeks before surgery. The primary endpoint was disease-free survival and the secondary endpoints included adverse events, HRQoL, and cost-effectiveness. In a HRQoL sub-study, subjects were assessed at baseline and 4 and 16 weeks after starting neoadjuvant LET, using the functional assessment of cancer therapy-breast and its ES subscale, and the hospital anxiety and depression scale. HRQoL and psychosocial distress were analyzed in the uncontrolled phase during 24-28 weeks of neoadjuvant LET therapy in the NEOS trial. From May 16, 2008, to December 14, 2011, 503 patients were recruited into the HRQoL sub-study. The full analysis set included 497 patients with a mean age of 63-years old. The questionnaire response rates at enrollment and 4 and 16 weeks were 94.4, 90.7, and 89.1 %, respectively. There were no significant changes in the FACT-G or B-trial outcome index over time, but the social and family well-being score and the ES subscale deteriorated significantly, and the number of patients with clinically significant hot flush increased significantly. Anxiety, depression, and emotional well-being improved significantly after neoadjuvant LET. Neoadjuvant endocrine therapy with LET had no impact on global HRQoL, but did influence endocrine-related symptoms such as hot flush. This study is registered as UMIN000001090.

1070 Background: Although nab-paclitaxel (nab-PTX) has shown superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), chemotherapy induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In a single arm Phase 2 trail (CA002-0LD), low dose nab-PTX (175mg/m2) every 3 weeks (q3w) demonstrated a good objective response rate (39.5%) without grade 3 or higher CIPN. Herein, we conducted multicenter randomized controlled study to evaluate optimal dose of nab-PTX comparing lower dose (LD or MD) to standard dose (SD). Methods: This study compared three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) in patients with HER2 negative metastatic breast cancer. Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses are estimated by the logistic regression. Optimal dose was selected by 2 step selection. At first, if hazard ratio (HR) for PFS was less than 0.75 or more than 1.33, the inferior dose was dropped. Then, if estimated incidence rate of grade 3/4 neurotoxicity exceed10%, that dose was also dropped. This trial is registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). Results: In this study, 141 patients were randomly assigned to SD (n = 47), MD (n = 46) or LD (n = 48). Median PFS was 6.66 vs 7.34 vs 6.82 months, respectively. HR was 0.73 (95% confidence interval (CI): 0.42-1.28) in MD vs SD. SD was dropped due to inferiority to MD. HR was 0.77 (95%CI 0.47-1.28) in LD vs SD, and 0.96 (95%CI 0.56-1.66) in LD vs MD. LD and MD were carried over to next step due to equivalence. Overall survival was not different among all dose arms. Rate of dose reduction by treatment course was significantly higher in SD arm. Estimated incidence of grade 3/4 neurotoxicity rate was 29.5% in SD, 14.0% in MD and 5.9% in LD. Final selected dose was LD 180mg/m2. HR-QOL results will be presented. Conclusions: Low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose with good clinical efficacy and tolerability for patients with MBC. Clinical trial information: C000012429.

PurposeMany breast cancer patients suffer from chemotherapy-induced hair loss. Accurate information about temporal changes in chemotherapy-induced hair loss is important for supporting patients scheduled to receive chemotherapy, because it helps them to prepare. However, accurate information, on issues such as the frequency of hair loss after chemotherapy, when regrowth starts, the condition of regrown hair, and the frequency of incomplete hair regrowth, is lacking. This study aimed to clarify the long-term temporal changes in chemotherapy-induced hair loss using patient-reported outcomes for chemotherapy-induced hair loss.MethodsWe conducted a multicenter, cross-sectional questionnaire survey. Disease-free patients who had completed adjuvant chemotherapy consisting of anthracycline and/or taxanes for breast cancer within the prior 5 years were enrolled from 47 hospitals and clinics in Japan. Descriptive statistics were obtained in this study. The study is reported according to the STROBE criteria.ResultsThe response rate was 81.5% (1511/1853), yielding 1478 questionnaires. Hair loss occurred in 99.9% of patients. The mean time from chemotherapy until hair loss was 18.0 days. Regrowth of scalp hair occurred in 98% of patients. The mean time from the completion of chemotherapy to the beginning of regrowth was 3.3 months. Two years after chemotherapy completion, the scalp-hair recovery rate was ConclusionsOur survey focused on chemotherapy-induced hair loss in breast cancer patients. We believe these results to be useful for patients scheduled to receive chemotherapy.

Aim: The objective of this study was to apply a scoring method to fine needle aspiration cytology on breast duct dilatation and cystic lesions, to set an optimum cut-off value to differentiate between benign and malignant cases, and to identify features useful for cell judgment. Materials and Methods: Samples were 23 preparations of specimens (12 benign and 11 malignant cases) suspected with intraductal lesions or cystic change by ultrasonography or mammography and cytology. The scoring system comprised the following 10 items, and each item was scored 1–3, with a total score of 10–30. Three items were concerning structural atypia: 1, scattered epithelial cells; 2, uneven irregular cluster edge; and 3, overlapping nuclei of epithelial cells, and seven items were concerning cellular atypia: 4, irregular nuclear size; 5, irregular nuclear morphology; 6, deep dyeing chromatin; 7, chromatin granularity; 8, chromatin distribution; 9, nucleolus; and 10, absence of myoepithelial cells. Results: (1) Scoring cut-off value: malignancy is to be suspected when the score is 20.75 or higher (diagnostic accuracy: 95.7%). (2) Findings useful for cancer judgment: the sensitivity of the following four findings was high: uneven irregular cluster edge, irregular nuclear overlapping, chromatin granularity, and absence of myoepithelial cells. (3) Correlation among the findings: the findings correlated with malignancy were as follows: scattered epithelial cells versus uneven irregular cluster edge (rs = 0.8). Conclusion: Cytological evaluation by scoring lesions accompanied by intraductal dilatation and cystic change was a useful method capable of differentiating between benign and malignant cases at a high accuracy.

Background: Zoledronic acid (ZOL) has been found to have a synergistic anti-proliferative effect when used in combination with antitumor drugs. We suggested that the addition of ZOL to neoadjuvant chemotherapy (CT) has potential anti-cancer benefit in postmenopausal patients with triple-negative breast cancer in JONIE-1 Trial (50% pCR rate in ZOL+CT: CTZ versus 0% in CT, p = 0.029). We analyzed the disease-free survival (DFS) as a secondary endpoint and baseline Ki67 levels between two groups. Methods: Women with Stage IIA-IIIB HER-2-negative breast cancer were randomly assigned 1:1 to CTZ group or CT group, CT was FEC100 q3w × 4 cycles followed by weekly paclitaxel for 12 cycles and ZOL 4mg was administered every 3-4 weeks. Among 188 patients recruited between March 2010 and April 2012 excluding 10 from the primary assessment, 178 patients were assessed. The aims of this study were to compare the relative efficacy or CTZ with the efficacy of CT in prolonging DFS in all patients and also to compare the pCR rates between baseline Ki67 high (20% and >20%) with Ki67 low ( Results: During a mean follow-up period of 34.4 months, breast cancer specific events (recurrence and death) occurred 17 participants, 7 in CTZ group and 10 in CT group. The 1-year, 2-year, and 3-year DFS rates were 97.7%, 88.4%, and 88.4% in CTZ versus 100%, 84.8%, and 81.1% in CT, respectively. In the ER positive cohort studied for Ki67 consist of 109 patients, 40 were in Ki67 low group and 69 were in Ki67 high group. Among Ki67 low group, number of pCR was none out of 18 in CTZ and 1 out of 22 in CT (p = .550). Among Ki high group, that was 6 out of 38 in CTZ and 3 out of 31 (p = .352). Conclusion: We could not find a modest improvement in disease-free survival compared the addition of ZOL to neoadjuvant CT with CT alone. Ki67 study for central analysis has been under investigation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-7.

Article, ACTA DERMATO-VENEREOLOGICA.96(6):830-831(2016)

A dimeric Baeyer-Villiger monooxygenase (BVMO) catalyzing the lactonization of 2-oxo-Δ 3 -4,5,5-trimethylcyclopentenylacetyl-coenzyme A (CoA), a key intermediate in the metabolism of camphor by Pseudomonas putida ATCC 17453, had been initially characterized in 1983 by Ougham and coworkers (H. J. Ougham, D. G. Taylor, and P. W. Trudgill, J. Bacteriol. 153:140–152, 1983). Here we cloned and overexpressed the 2-oxo-Δ 3 -4,5,5-trimethylcyclopentenylacetyl-CoA monooxygenase (OTEMO) in Escherichia coli and determined its three-dimensional structure with bound flavin adenine dinucleotide (FAD) at a 1.95-Å resolution as well as with bound FAD and NADP + at a 2.0-Å resolution. OTEMO represents the first homodimeric type 1 BVMO structure bound to FAD/NADP + . A comparison of several crystal forms of OTEMO bound to FAD and NADP + revealed a conformational plasticity of several loop regions, some of which have been implicated in contributing to the substrate specificity profile of structurally related BVMOs. Substrate specificity studies confirmed that the 2-oxo-Δ 3 -4,5,5-trimethylcyclopentenylacetic acid coenzyme A ester is preferred over the free acid. However, the catalytic efficiency ( k cat / K m ) favors 2- n -hexyl cyclopentanone (4.3 × 10 5 M −1 s −1 ) as a substrate, although its affinity ( K m = 32 μM) was lower than that of the CoA-activated substrate ( K m = 18 μM). In whole-cell biotransformation experiments, OTEMO showed a unique enantiocomplementarity to the action of the prototypical cyclohexanone monooxygenase (CHMO) and appeared to be particularly useful for the oxidation of 4-substituted cyclohexanones. Overall, this work extends our understanding of the molecular structure and mechanistic complexity of the type 1 family of BVMOs and expands the catalytic repertoire of one of its original members.