[Show abstract][Hide abstract] ABSTRACT: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been found to have therapeutic potential for treating cancers associated with impaired DNA repair capabilities, particularly those with deficiencies in the homologous recombination repair (HRR) pathway. Histone deacetylases (HDACs) are important for enabling functional HRR of DNA by regulating the expression of HRR-related genes and promoting the accurate assembly of HRR-directed sub-nuclear foci. Thus, HDAC inhibitors have recently emerged as a therapeutic agent for treating cancer by inhibiting DNA repair. Based on this, HDAC inhibition could be predicted to enhance the anti-tumor effect of PARP inhibitors in cancer cells by blocking the HRR pathway.
We determined whether suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, could enhance the anti-tumor effects of olaparib on breast cancer cell lines using a cytotoxic assay, cell cycle analysis, and Western blotting. We evaluated how exposure to SAHA affects the expression of HRR-associated genes. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was assessed. Induction of autophagy was monitored by imaging green fluorescent protein-tagged microtubule-associated protein 1A/1B-light chain 3 (LC3) expression following co-treatment with olaparib and SAHA. These in vitro data were validated in vivo using a human breast cancer xenograft model.
Triple-negative breast cancer cell (TNBC) lines showed heterogeneous responses to the PARP and HDAC inhibitors. Co-administration of olaparib and SAHA synergistically inhibited the growth of TNBC cells that expressed functional Phosphatase and tensin homolog (PTEN). This effect was associated with down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. The combined anti-tumor effect of olaparib and SAHA was also observed in a xenograft model. These data suggest that PTEN expression in TNBC cells can sensitize the cell response to simultaneous inhibition of PARP and HDAC both in vitro and in vivo.
Our findings suggest that expression of functional PTEN may serve as a biomarker for selecting TNBC patients that would favorably respond to a combination of olaparib with SAHA. This provides a strong rationale for treating TNBC patients with PTEN expression with a combination therapy consisting of olaparib and SAHA.
Breast cancer research: BCR 12/2015; 17(1):534. DOI:10.1186/s13058-015-0534-y · 5.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Pegylated granulocyte-colony-stimulating factor (G-CSF) is frequently used to prevent febrile neutropenia (FN) in patients undergoing chemotherapy with a high risk of myelosuppression. This phase II/III study was conducted to determine the adequate dose of pegteograstim, a new formulation of pegylated G-CSF, and to evaluate the efficacy and safety of pegteograstim compared to pegfilgrastim.
In the phase II part, 60 breast cancer patients who were undergoing DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy were randomly selected to receive a single subcutaneous injection of 3.6 or 6.0 mg pegteograstim on day 2 of each chemotherapy cycle. The phase III part was seamlessly started to compare the dose of pegteograstim at selected in phase II with 6.0 mg pegfilgrastim in 117 breast cancer patients. The primary endpoint of both the phase II and III parts was the duration of grade 4 neutropenia in the chemotherapy cycle 1.
The mean duration of grade 4 neutropenia for the 3.6 mg pegteograstim (n = 33) was similar to that for the 6.0 mg pegteograstim (n = 26) (1.97 ± 1.79 days vs. 1.54 ± 0.95 days, p = 0.33). The 6.0 mg pegteograstim was selected to be compared with the 6.0 mg pegfilgrastim in the phase III part. In the phase III part, the primary analysis revealed that the efficacy of pegteograstim (n = 56) was non-inferior to that of pegfilgrastim (n = 59) [duration of grade 4 neutropenia, 1.64 ± 1.18 days vs. 1.80 ± 1.05 days; difference, -0.15 ± 1.11 (p = 0.36, 97.5 % confidence intervals = 0.57 and 0.26)]. The time to the absolute neutrophil count (ANC) recovery of pegteograstim (≥2000/μL) was significantly shorter than that of pegfilgrastim (8.85 ± 1.45 days vs. 9.83 ± 1.20 days, p < 0.0001). Other secondary endpoints showed no significant difference between the two groups. The safety profiles of the two groups did not differ significantly.
Pegteograstim was shown to be as effective as pegfilgrastim in the reduction of chemotherapy-induced neutropenia in the breast cancer patients who were undergoing chemotherapy with a high risk of myelosuppression.
Supportive Care in Cancer 10/2015; DOI:10.1007/s00520-015-2963-7 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Current nodal staging system for extrahepatic bile duct (EHBD) cancer is controversial. The number of metastatic lymph nodes (mLN) and lymph node ratio (LNR) has been studied for the assessment of the nodal status in many other gastrointestinal cancers, but there are few studies on assessing the prognostic impact of these parameters in EHBD cancer.
We retrospectively reviewed 239 consecutive patients who underwent curative resection followed by adjuvant chemoradiotherapy for adenocarcinoma of EHBD from 1995 to 2009 in our institution. The prognostic value of the number of mLN and LNR was evaluated by adjusting for other known factors. Optimal cutoff points were determined using maximally selected chi-square test.
Lymph node metastasis was found in 77 (32 %) patients. Univariate analysis for overall survival (OS) revealed both the number of mLN (0 vs. 1-3 vs. ≥4; p < 0.001) and LNR (<0.2 vs. ≥0.2; p < 0.001) as significant prognosticators. Multivariate analysis demonstrated that the number of mLN was an independent prognostic factor, whereas LNR was not. The estimated 5-year OS was 48.7 % for patients with negative nodes, 33.4 % for patients with 1-3 mLN, and 9.1 % for patients with 4 or more mLN (p < 0.001).
The number of mLN is a powerful parameter to predict survival in the EHBD cancer, which is more reliable than LNR. As for many other gastrointestinal cancers, further classification of node positive patients based on the number of mLN seems to be useful and may provide precise information.
Journal of Gastrointestinal Surgery 08/2015; DOI:10.1007/s11605-015-2898-9 · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Profound methylation of CpG islands constitutes a distinct molecular subtype of colorectal cancer (CRC). The frequencies of methylation in CRC vary according to clinico-pathological characteristics including sex. However, interaction between these characteristics and prognostic influence of methylation status has not been clearly defined. We have investigated the prognostic role of promoter methylation using eight CpG island methylator phenotype (CIMP) markers in 497 stage II or III CRC patients who underwent curative resection followed by adjuvant FOLFOX. Overall survival (OS) and disease-free survival (DFS) were compared between subgroups classified by methylation status, and interactions with clinico-pathological features were analyzed.
CIMP-high (≥5 methylated loci) and concurrent methylation in NEUROG1 and CDKN2A (p16) were found in 5.8 and 7.9 % of patients, respectively. Although CIMP-high status was not associated with survival, concurrent methylation in NEUROG1 and CDKN2A (p16) was associated with shorter OS and DFS. Moreover, the prognostic role of the concurrent methylation was different among sex. The negative prognostic impact was only observed in male but not in female (interaction p value = 0.026 for OS and 0.011 for DFS). In male, the 5-year OS was 61.6 % in concurrent methylation (+) and 91.7 % in concurrent methylation (-) (p < 0.001) whereas it was 95.0 and 92.8 % in female, respectively (p = 0.78).
Concurrent methylation in NEUROG1 and CDKN2A is associated with poor survival in CRC treated with adjuvant FOLFOX. Interaction analysis indicates that the prognostic role is different according to sex.
[Show abstract][Hide abstract] ABSTRACT: In advanced gastric cancer (AGC), HER2 is a validated therapeutic target. However, the metabolic landscape of AGC based on HER2 status has not been reported. Furthermore, the prognostic value of HER2 in AGC is under debate. The purpose of this study was to determine the metabolic landscape and prognosis on the basis of HER2 status in AGC.
We analyzed 866 AGC patients treated with palliative chemotherapy and whose HER2 status was evaluated. HER2 positivity was defined as HER2 IHC 3+ or HER2/CEP17 ratio ≥2. Among them, 363 patients were evaluated with (18)F FDG-PET before chemotherapy. We analyzed mSUV (maximal standardized uptake value) according to HER2 status and clinical outcomes.
Among 866 patients, 225 (26.0 %) had HER2+ GC. The mSUV of HER2+ GC was significantly higher than that of HER2- GC (12.6 vs. 8.7, p < 0.001). Increased HER2 IHC positivity was correlated with increased mSUV (IHC-: 8.1, IHC 1+: 8.2, 2+: 11.4, 3+: 13.2, p < 0.001). Excluding HER2+ patients who received HER2-targeting agents, OS of patients was not different by HER2 status (12.5 vs. 11.9 months, p = 0.688). However, according to tumor metabolism, patients with higher mSUV showed worse OS regardless of HER2 positivity (mSUV < 12.8:14.8, ≥12.8:8.6 months, p < 0.001).
Tumor metabolism of AGC adversely influenced OS under treatment with cytotoxic chemotherapy. Tumor metabolism was higher in HER2+ AGC than HER2-. However, HER2 was not a prognostic factor in patients who received chemotherapy without HER2-targeting agents.
Gastric Cancer 05/2015; DOI:10.1007/s10120-015-0504-1 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This is a phase I/II study of second-line chemotherapy with paclitaxel and irinotecan in fluoropyrimidine- and platinum-pretreated patients with metastatic or recurrent gastric cancer.
Phase I part with a standard 3 + 3 dose-escalation design was conducted to define the recommended phase II dose (RP2D) using four predefined dose levels of paclitaxel and irinotecan. The efficacy of RP2D was evaluated in a phase II part.
In phase I part, 12 patients were enrolled. Dose-limiting toxicity was not observed. The RP2D was established as level 4 (paclitaxel-135 mg/m(2) and irinotecan-160 mg/m(2), every 3 weeks). In phase II part, 27 patients were enrolled. Thirty patients, including three patients at dose level 4 in the phase I part, were analyzed for efficacy. There was no complete response. Partial response and stable disease were reported in four and 16 patients, respectively (response rate 13.3 %, 95 % CI 0.0-25.5 %; disease control rate 66.6 %, 95 % CI 49.0-83.0 %). The median time to progression and overall survival was 3.0 months (95 % CI 1.8-4.2) and 10.1 months (95 % CI 6.6-13.6), respectively. Grade 3/4 toxicities included neutropenia (2 patients, 7.4 %), thrombocytopenia (1, 3.7 %), neutropenic fever (1, 3.7 %), and diarrhea (1, 3.7 %). There were no treatment-related deaths.
The RP2D of the paclitaxel and irinotecan combination is paclitaxel (135 mg/m(2)) and irinotecan (160 mg/m(2)), every 3 weeks. This combination as a second-line treatment for advanced gastric cancer shows tolerable toxicity and modest efficacy.
Cancer Chemotherapy and Pharmacology 04/2015; 75(6). DOI:10.1007/s00280-015-2732-9 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A causal relationship between diabetes mellitus (DM) and pancreatic cancer (PC) is well established. However, in patients with advanced pancreatic cancer (APC) who receive palliative chemotherapy, the impact of DM on the prognosis of APC is unclear.
We retrospectively enrolled APC patients who received palliative chemotherapy between 2003 and 2010. The patients were stratified according to the status of DM, in accordance with 2010 DM criteria (AHA/ADA). DM at least 2 years' duration prior to diagnosis of APC was defined as remote-onset DM (vs recent-onset).
Of the 349 APC patients, 183 (52.4%) had DM. Among the patients with DM, 160 patients had DM at the time of diagnosis of APC (remote-onset, 87; recent-onset, 73) and the remaining 23 patients developed DM during treatment of APC. Ultimately, 73.2% (134/183) of patients with DM received antidiabetic medication, including metformin (56 patients, 41.8%), sulfonylurea (62, 45.5%), and insulin (43, 32.1%). In multivariate analysis, cancer extent (HR, 1.792; 95% CI, 1.313-2.445; P<0.001) showed association with decreased overall survival (OS), whereas a diagnosis of DM (HR, 0.788; 95% CI, 0.615-1.009; P=0.059) conferred positive tendency on the OS. Metformin treatment itself conferred better OS in comparison within DM patients (HR 0.693; 95% CI, 0.492-0.977; P=0.036) and even in all APC patients (adjusted HR 0.697; 95% CI, 0.491-1.990; P=0.044).
s For APC patients receiving palliative chemotherapy, metformin treatment is associated with longer OS. Patients with DM tend to survive longer than those without DM.
Cancer Research and Treatment 03/2015; DOI:10.4143/crt.2014.292 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Weight loss during chemotherapy is a significant prognostic factor for poor survival in patients with advanced gastric cancer (AGC). However, in most studies, weight loss was measured at the end of chemotherapy, limiting its clinical use. In this study, we evaluated whether weight loss during the first month of chemotherapy could predict survival outcomes in patients with AGC.
We analyzed 719 patients with metastatic or recurrent AGC who were receiving palliative chemotherapy. We calculated the initial body mass index (BMIi), percent weight loss after 1 month of chemotherapy (ΔW 1m), percent weight loss after last administration of chemotherapy (ΔW end), and average weight loss per month during chemotherapy (ΔW/m). We correlated these data with overall survival (OS) by receiver-operating characteristic (ROC) curves and Kaplan-Meier curves, and performed a subgroup analysis using Cox regression.
The probabilities of longer OS had stronger correlations with ΔW/m and ΔW 1m than with ΔW end or BMIi. A significant positive correlation between ΔW 1m and ΔW/m (r (2) = 0.591, p < 0.001) was observed. Median OS of patients with ΔW 1m more than 3 % was significantly shorter than in patients with less weight loss (OS: 9.7 vs. 16.3 months, p < 0.001). Subgroup analysis revealed that ΔW 1m accompanied poor survival irrespective of other clinical characteristics.
Weight loss at the very first month of palliative chemotherapy could predict unfavorable survival outcomes in AGC.