Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201.

Background: Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment. Methods: Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay. Results: Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]. Conclusions: Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

Therapeutic Benefits of Ipilimumab among Japanese Patients with Nivolumab-Refractory Mucosal Melanoma: A Case Series Study.

The antibodies targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have provided survival benefits in patients with advanced malignant melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab are considered superior to the anti-CTLA-4 antibody ipilimumab as first-line therapy, suggesting that ipilimumab should be administered to patients with anti-PD-1 antibody-refractory melanoma in the second-line setting. However, there is limited evidence regarding the efficacy and safety of ipilimumab after disease progression on anti-PD-1 antibody therapy. Moreover, in patients with mucosal melanoma, a rare and aggressive subtype, evidence is extremely poor. This study aimed to clarify the efficacy and safety of ipilimumab among Japanese patients with nivolumab-refractory advanced mucosal melanoma. We retrospectively analyzed the seven patients with advanced mucosal melanoma who were treated with ipilimumab after disease progression on nivolumab at our hospital between September 2015 and December 2017. No patient achieved complete response or partial response to ipilimumab therapy. However, six patients achieved stable disease, and of these patients, three achieved a decline in the tumor size. All the three patients with a decline in tumor size developed grade 3 toxicity: two patients developed colitis and one patient experienced alanine aminotransferase elevation. The median progression-free survival (PFS) for prior nivolumab therapy was 148 days. The median PFS for ipilimumab therapy after disease progression with nivolumab was 193 days. The median overall survival was 661 days. In conclusion, although even partial response was undetectable with ipilimumab therapy, ipilimumab could produce additional PFS among nivolumab-refractory advanced mucosal melanoma patients.

Predictive factors for the efficacy of the second taxane treatment in patients with advanced cancer.

PURPOSE: Research has revealed that some patients who develop resistance to the first taxane treatment exhibit a moderate response to the second taxane treatment (incomplete cross-resistance between paclitaxel and docetaxel). However, which patients are most likely to respond to the second treatment remains unclear. The aim of this study was to determine the predictive factors for the efficacy of the second taxane treatment in patients resistant to the first. PATIENTS AND METHODS: We enrolled patients treated with paclitaxel and docetaxel (n=31) in this study. Using univariate and multivariate analyses, we determined the predictive factors for the efficacy of the second taxane treatment. Then, we assigned patients to one of the three groups: 1) those with a partial response (PR) to the first taxane treatment who subsequently became refractory (PR group); 2) those whose response was stable disease (SD) and subsequently became refractory (SD group); and 3) those whose response was the progression of the disease with the first taxane treatment (progression disease [PD] group). Furthermore, the response rates were assessed for each group. All statistical analyses were performed using JMP 11. RESULTS: Responses to the first taxane treatment considerably correlated with the efficacy of the second treatment in patients with a PR to the first taxane treatment (P=0.0061, univariate analysis; P=0.0056, multivariate analysis). In addition, response rates to the second taxane treatment in the PR, SD, and PD groups were 33.3%, 0%, and 0%, respectively. CONCLUSION: The response to the first taxane treatment was a predictive factor for the efficacy of the second taxane treatment in patients with a PR to the first. Thus, the second treatment is highly recommended for patients who exhibit tumor shrinkage (a PR) by the first treatment.

Efficacy and Safety of Trastuzumab in Combination with S-1 and Cisplatin Therapy for Japanese Patients with HER2-Positive Advanced Gastric Cancer: Retrospective Analysis.

The combinations of oral fluoropyrimidines and cisplatin such as capecitabine and cisplatin (XP) or S-1 and cisplatin (SP) are regarded as a standard therapy against unresectable, recurrent, or advanced gastric cancer (AGC). Especially, SP is the most common regimen against AGC in Japan. For patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC, trastuzumab, a monoclonal antibody targeting HER2 antibody, is additionally used in combination. Although trastuzumab in combination with XP (trastuzumab-XP) have been widely accepted, the efficacy of trastuzumab in combination with SP (trastuzumab-SP) lacks sufficient verification. The aim of the present study is to validate the comparability of trastuzumab-SP to trastuzumab-XP. Patients with HER2-positive AGC were assigned to the trastuzumab-XP or trastuzumab-SP group. We then retrospectively compared the efficacy and safety between both groups. As a first-line chemotherapy, trastuzumab in combination with XP or SP was administered to 58 patients: 28 with trastuzumab-XP and 30 with trastuzumab-SP. In the trastuzumab-XP group, response rate (RR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) were 39.3%, 89.3%, 7.9 months, and 20.0 months, respectively. In the trastuzumab-SP group, RR, DCR, mPFS and mOS were 50.0%, 86.7%, 6.9 months, and 16.7 months, respectively. No significant difference in efficacy was observed between both groups. Severe hand-foot syndrome was observed more frequently in the trastuzumab-XP group than in the trastuzumab-SP group (14.3% vs. 0%, p = 0.05). Trastuzumab in combination with SP is a potential first-line therapeutic option for patients with HER2-positive AGC.

Retrospective analysis on the clinical outcomes of recombinant human soluble thrombomodulin for disseminated intravascular coagulation syndrome associated with solid tumors.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) has been established and introduced in the clinic as a standard treatment for disseminated intravascular coagulation (DIC). However, the efficacy and safety of rTM for DIC associated with solid tumors (DIC-STs) have not been fully established. Here, we performed a retrospective analysis of the clinical outcomes of rTM for DIC-STs and considered a treatment strategy with rTM for DIC-STs. METHODS: Patients with DIC-STs between November 2009 and March 2016 in 2 cancer core hospitals were retrospectively analyzed. Data, including patient background, treatment course, and clinical outcomes of rTM for DIC-STs, were extracted. The clinical outcomes were evaluated by comparing the DIC score, resolution rate, and overall survival (OS) duration. RESULTS: The study included 123 patients with DIC-STs. The median OS in all patients was 41 days. The DIC resolution rate was 35.2%. DIC scores and DIC-related blood test data (fibrin degradation product and prothrombin time-international normalized ratio) significantly improved at the end of rTM administration (P < 0.001). The OS duration was longer in patients who were treated with chemotherapy after DIC onset than in those who were not treated with chemotherapy (median, 178 days vs. 17 days, P < 0.001). In both univariate and multivariate analyses, chemotherapy after DIC onset showed the strongest association with OS. CONCLUSIONS: rTM can at least temporarily improve or maintain the state of DIC-STs. It is suggested that prolongation of survival can be expected when control of DIC and treatment of the underlying disease are compatible.

Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines.

Cell cycle control is a promising target in cancer treatments, and some small-molecule cyclin-dependent kinase (CDK) inhibitors have exhibited clinical effectiveness. However, no biomarkers predictive of efficacy have been developed. Recent studies have revealed that CDK inhibitor (CKI) proteins, such as p27 and p16, also induced cytoprotective autophagy in cancer cells. However, it is unclear whether small-molecule CKIs also induce autophagy in solid tumors, as induced autophagy promotes cancer cell survival. In this study, we revealed that a CDK4 inhibitor and a CKI with a broad range of targets (flavopiridol) induced autophagy in some, but not all, solid cancer cell lines. Autophagy induction by CDK4 inhibitor was observed in BT474, MDA-MB435S, SKBr3 (derived from breast cancer), A431 (derived from epidermoid cancer), and SW480 (derived from colorectal cancer) cell lines. No such autophagy was observed in MCF7, MDA-MB231 (derived from breast cancer), NCI-N87 (derived from gastric cancer), and KMST-6 (derived from a fibroblast). In the cell lines showing autophagy, which was induced by CDK4 inhibitor, the combination of CDK4 inhibitor and autophagy inhibition by either chloroquine (CQ) or knockdown of ATG5 or BECN1 induced apoptosis. However, it did not induce apoptosis in the cell lines in which autophagy was not induced by CDK4 inhibitor. These findings indicate that the autophagy induced by CDK4 inhibitor mimics stress-induced autophagy in some solid cancer cell lines. The combination of a small-molecule CKI involved in G1/S arrest and an autophagy inhibitor leads to a synthetic lethal interaction and could become a new antitumor strategy for solid tumors showing cytoprotective autophagy induced by small-molecule CKIs.

The G8 screening tool enhances prognostic value to ECOG performance status in elderly cancer patients: A retrospective, single institutional study.

BACKGROUND: Some elderly cancer patients, even with good Eastern Cooperative Oncology Group performance status (ECOG-PS), have poor survival outcomes and cannot tolerate standard therapy. Few studies have detailed the associations between the G8 screening tool, ECOG-PS, and overall survival (OS) in such patients. METHODS: Cancer patients, aged 70 years or older, were assessed for G8 and classified into three groups according to their G8 score: <11 as the low score group, 11-14 as the intermediate score group, and >14 as the high score group. We retrospectively analyzed the association between G8 score and OS in all patients and for each ECOG-PS-categorized group. RESULTS: Out of 264 enrolled patients, most patients (87%) with solid tumor were categorized as TNM stage IV. ECOG-PS was 0 or 1 in 215 patients and ≥2 in 48; there was missing data for one patient. Among all patients, the low score group with a median OS of 7.7 months survived significantly less than both the high score group with a median OS of 25.6 months [Hazard ratio (HR) 3.48; 95% confidence interval (CI), 1.96-6.63; p < 0.0001] and the intermediate score group with a median of 15.6 months (HR 1.83; 95% CI, 1.28-2.65; p < 0.001). In the multivariate analysis, TNM stage and G8 score were independent prognostic factors for OS. When patients with an ECOG-PS of 0 or 1 were analyzed, patients with a lower G8 score showed significantly shorter OS than patients with a higher score when any two groups were compared. CONCLUSION: This novel classification of the G8 score contributes to prompt identification of patients with poor prognosis and improved the prognostic value of ECOG-PS. Using G8 with ECOG-PS may be helpful in deciding treatment for elderly patients with advanced cancer.

Efficacy and safety of gemcitabine plus docetaxel in Japanese patients with unresectable or recurrent bone and soft tissue sarcoma: Results from a single-institutional analysis.

BACKGROUND: Combination therapy with gemcitabine and docetaxel has been reported to be a good therapeutic strategy for patients with soft tissue sarcoma. The aim of the present study was to analyze the efficacy and toxicity of gemcitabine with docetaxel in Japanese patients with advanced bone and soft tissue sarcoma. PATIENTS AND METHODS: We retrospectively analyzed the effect of gemcitabine and docetaxel therapy on overall response, progression-free survival, overall survival, and toxicity in 42 patients with bone or soft tissue sarcoma who had received the therapy between October 2006 and September 2015, at Tohoku University Hospital. RESULTS: The median age was 55 years; 23 patients were men, and 19 were women. Eight had bone sarcoma and 34 had soft tissue sarcoma. Forty patients (95%) had previously been treated with one or more chemotherapeutic regimens. The overall response rate was 6.9% and the disease control rate was 55%. The median progression-free survival was 2.3 months and the median overall survival was 14.3 months. Grade 3 or more neutropenia and febrile neutropenia were observed in 74% and 4.8% of all patients, respectively. CONCLUSION: The response rate was lower and myelosuppression was more frequently observed than in other previous reports. On the other hand, most of toxicities were enough manageable. In addition, some patients had long survival with a good response. Our study supports the notion that gemcitabine and docetaxel therapy is a good therapeutic option for treating patients with advanced soft tissue sarcoma as well as bone sarcoma, also in Asian populations.

Efficacy and Safety Assessment of Paclitaxel in Patients with Docetaxel-Resistant Esophageal Squamous Cell Carcinoma.

BACKGROUND: Incomplete cross-resistances between paclitaxel (PTX) and docetaxel (DTX) has been demonstrated in several types of cancer. The objective of the present study was to assess the existence of cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. METHODS: Patients in the PTX group received PTX without DTX pretreatment, patients in the prior DTX (Pr-DTX) group received PTX after the development of resistance to DTX, and patients in the DTX group received DTX without subsequent PTX treatment. RESULTS: A total of 73 patients were enrolled. The response rates to PTX in the PTX and Pr-DTX groups were 22.7 and 20.0%, respectively. The median progression-free survival times from the first day of PTX treatment in the PTX and Pr-DTX groups were 113 (95% CI 56-154) and 97 days (95% CI 36-189), respectively. The median overall survival times from the first day of DTX treatment in the Pr-DTX and DTX groups were 315 (95% CI 124-453) and 148 days (95% CI 139-177), respectively. CONCLUSIONS: There is no or incomplete clinical cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. Replacement of DTX with PTX is a suitable treatment option for patients with DTX-resistant esophageal squamous cell carcinoma.

Suppression of FUT1 attenuates cell proliferation in the HER2-overexpressing cancer cell line NCI-N87.

Lewis Y (LeY) antigen is an oligosaccharide that is highly expressed at the cell surface in various human cancers. Increased LeY expression activates epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) and promotes cell proliferation in EGFR-overexpressing cells. However, the effect of downregulation of LeY expression on cell proliferation in HER2-overexpressing cells remains unknown. FUT1 encodes α1,2-fucosyltransferase, a key enzyme for LeY synthesis. We knocked down FUT1 by short interfering RNA (siRNA) in four HER2-overexpressing human cancer cell lines, including NCI-N87, MKN7, SKBr3 and BT474. We investigated whether downregulation of LeY and alteration in the glycosylation status of these cells affect cell proliferation and HER2 activation. Knocking down FUT1 expression markedly inhibited proliferation of NCI-N87, which highly expressed EGFR and was sensitive to EGFR deprivation. Furthermore, FUT1 siRNA downregulated the total amount of HER2 protein, phosphorylation of HER2 and EGFR, and phosphorylation of extracellular signal-regulated kinase (ERK) in this cell line. Moreover, the marked downregulation of phosphorylation of HER2 and ERK was observed following short-time EGF-stimulation. These effects were not observed in the other three cell lines. Our results suggest that knockdown of FUT1 downregulates HER2 signaling via EGFR downregulation. FUT1 may serve as a new molecular target for HER2-overexpressing human cancers with activated EGFR signaling.

Contribution of autophagic cell death to p53-dependent cell death in human glioblastoma cell line SF126.

Apoptosis and autophagic cell death are programmed cell deaths that are involved in cell survival, growth, development and carcinogenesis. p53, the most extensively studied tumor suppressor, regulates apoptosis and autophagy by transactivating its downstream genes. It also stimulates the mitochondrial apoptotic pathway and inhibits autophagy in a transactivation-independent manner. However, the contribution of apoptosis and autophagic cell death to p53-dependent cell death is unclear. Using wild-type (WT) and mutant (MT) p53 inducible cell lines in TP53-null SF126 glioblastoma cells, we examined the apoptosis and autophagic cell death induced by p53. WT p53 expression in SF126 cells induced apoptosis and autophagy, and reduced the cell number. An autophagy inhibitor reduced autophagy, increased the S-phase fraction, and attenuated the inhibition of cell proliferation induced by WT p53. Pan-caspase inhibitor reduced apoptosis but showed weaker inhibition of cell proliferation than the autophagy inhibitor. We concluded that p53-dependent cell death in SF126 cells comprises caspase-dependent and caspase-independent apoptosis and autophagic cell death, and the induction of autophagy as well as apoptosis could be a new strategy to treat some type of WT p53-retaining tumors.