Yuji Miyamoto

Molecular Pathways: Cachexia Signaling-A Targeted Approach to Cancer Treatment.

Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass, which negatively affects quality of life and portends a poor prognosis. Numerous molecular substrates and mechanisms underlie the dysregulation of skeletal muscle synthesis and degradation observed in cancer cachexia, including proinflammatory cytokines (TNFα, IL1, and IL6), and the NF-κB, IGF1/AKT/mTOR, and myostatin/activin–SMAD pathways. Recent preclinical and clinical studies have demonstrated that anti-cachexia drugs (such as MABp1 and soluble receptor antagonist of myostatin/activin) not only prevent muscle wasting but also may prolong overall survival. In this review, we focus on the significance of cachexia signaling in patients with cancer and highlight promising drugs targeting tumor cachexia in clinical development. Clin Cancer Res; 22(16); 3999–4004. ©2016 AACR.

Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab: Results from TRIBE and FIRE-3 trials

PURPOSEnThe most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF-associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC).nnnPATIENTS AND METHODSnPatients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (nxa0=xa0219, discovery cohort) and the FIRE-3 trial (nxa0=xa0234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, nxa0=xa0204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing.nnnRESULTSnThe FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2-3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02-0.73; Pxa0=xa00.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2-3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14-1.11; Pxa0=xa00.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45-4.04; Pxa0=xa00.60).nnnCONCLUSIONnThis is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab.

Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer.

BACKGROUNDnTrifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer (mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in FTD metabolism and TPI excretion could predict outcome in patients with mCRC treated with TAS-102.nnnPATIENTS AND METHODSnWe investigated three different cohorts: a training cohort (nxa0=xa052) and a testing cohort (nxa0=xa0129) both receiving TAS-102xa0and a control cohort (nxa0=xa052) receiving regorafenib. SNPs of TK1, ENT1, CNT1, MATE1, MATE2xa0and OCT2 were analysed byxa0polymerase chain reaction-based direct DNA sequencing.nnnRESULTSnIn the training cohort, patients with any ENT1 rs760370xa0G allele had a significantly longer progression-free survival (PFS; 3.5 versusxa02.1 months, respectively, hazard ratio [HR] 0.44, Pxa0=xa00.004) and overall survival (OS; 8.7 versusxa05.3 months, respectively, HR 0.27, Pxa0=xa00.003) than the A/A genotype. These findings were validated in the testing cohort (Pxa0=xa00.021 and 0.009 for PFS and OS, respectively). In addition, the combination of ENT1 rs760370, MATE1 rs2289669xa0and OCT2 rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both cohorts (Pxa0<xa00.001 for PFS and OS in the training cohort; Pxa0=xa00.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant differences were observed in the control group.nnnCONCLUSIONSnThe combination of ENT1, MATE1xa0and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.

Impact of sex, age, and ethnicity/race on the survival of patients with rectal cancer in the United States from 1988 to 2012

Most studies report on colon and rectal cancers collectively, even though biologic and prognostic differences exist between these disease entities. Here, we investigated the effects of sex, age, and ethnicity/race on rectal cancer (RC) mortality by stage focusing on differences before and after 2004. Using the SEER database, we identified 105,511 patients diagnosed with RC from 1988-2012. Main outcomes were disease-specific survival (DSS) and overall survival (OS). In patients with stage I-III RC, women achieved a longer DSS (HR 0.87, P < 0.001) than men, independent of age, from 1988-2012. In stage IV disease, the sex disparity favoring women was limited to the age 18-44 yr cohort (DSS HR 0.79, P < 0.001). The sex difference in DSS (Pinteraction = 0.009) was significantly reduced from 2004 to 2012 across all ages. Hispanics and Native Americans with locoregional RC had inferior DSS relative to Whites from 1988-2003, but these differences were not evident from 2004-2012 (Pinteraction = 0.001). Additionally, Asians with stage I-III RC had superior DSS from 2004 on compared to Whites. Mortality in African American patients improved modestly overall and remained significantly higher than other ethnicities/races across all stages. Sex disparities have narrowed in patients with metastatic RC, but persist in patients with stage I-III disease. These differences are most evident among young patients (18-44 years), where sex disparities have even widened in stage I-III disease. While outcomes have improved for Asians, Hispanics, and Native Americans with stage I-III rectal cancer, black-white disparities remain in all disease stages.

A polymorphism within the vitamin D transporter gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab. Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed. Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D–binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable (P = 0.001) and multivariable analyses (P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P = 0.033) and multivariable analyses (P = 0.046). Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784–93. ©2017 AACR.

A novel antimetabolite: TAS-102 for metastatic colorectal cancer

ABSTRACT TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI). TAS-102 has been shown to significantly improve overall survival and progression-free survival in patients with refractory metastatic colorectal cancer (mCRC) in placebo-controlled randomized phase II and III trials. The current review summarizes mechanisms of action, pharmacokinetics/dynamics and preclinical and clinical data of TAS-102 in colorectal cancer. TAS-102 is a new salvage-line treatment option for patients with mCRC. TAS-102 is well tolerated and has great potential in future clinical drug combination therapies.

Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer

The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type‐I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab‐based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5 and IRF7 were tested for the association with RR, PFS, and OS in KRAS‐wild type mCRC patients. Patients treated with FOLFIRIu2009+u2009cetuximab or FOLFIRIu2009+u2009bevacizumab in the FIRE‐3 trial served as a discovery set (FIRE3‐Cet, nu2009=u2009244) or a control set (FIRE3‐Bev, nu2009=u2009246), respectively. Patients treated with FOLFOX or SOXu2009+u2009cetuximab in the JACCRO‐CC05/06 trial served as a validation set (JACCRO, nu2009=u200976). Genomic DNA isolated from tumor tissue samples was analyzed by PCR‐based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, pu2009=u20090.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, pu2009=u20090.005, multivariate: HR 2.02, 95% CI: 1.14–3.55, pu2009=u20090.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab‐based chemotherapy in mCRC patients.

Clinical significance of tlr1 i602s polymorphism for patients with metastatic colorectal cancer treated with folfiri plus bevacizumab

The purpose of this study was to evaluate the clinical significance of single-nucleotide polymorphisms in TLR1, TLR2, TLR6, and TAK1 in patients with metastatic colorectal cancer (mCRC). We genotyped 9 SNPs of TLR1, TLR2, TLR6, and TAK1 in mCRC patients treated with first-line FOLFIRI (combination therapy of irinotecan, 5-fluorouracil, and folinic acid) plus bevacizumab, using a discovery cohort (TRIBE trial, n = 228) and a validation cohort (FIRE-3 trial, n = 297), and analyzed for the association with response rate (RR), progression-free survival (PFS), and overall survival (OS). There was a significant association of TLR1 rs5743618 (T1805G) with the clinical outcome. In the TRIBE cohort, a homozygous wild-type genotype (T/T) associated with a significantly lower RR compared with variant T/G and G/G genotypes (43% vs. 62%, P = 0.025), and this observation was validated in the FIRE-3 cohort (46% vs. 65%, P = 0.021). In addition, those patients with the T/T genotype had significantly worse PFS (median, 8.2 vs. 10.5 months; HR, 1.57; 95% CI, 1.09–2.28, P = 0.014) and OS (median: 19.9 vs. 27.9 months; HR, 1.63; 95% CI, 1.14–2.35, P = 0.007), compared with those with other genotypes in the TRIBE cohort. These differences remained statistically significant in multivariate analysis. Our data suggest that TLR1 rs5743618 could serve as a predictor of clinical response to FOLFIRI plus bevacizumab in patients with mCRC. Mol Cancer Ther; 15(7); 1740–5. ©2016 AACR.

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand–Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib

Background The C‐C motif chemokine ligand 5/C‐C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. Patients and Methods We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway‐related genes were analyzed by PCR‐based direct sequencing. Results CCL4 rs1634517 and CCL3 rs1130371 were associated with progression‐free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression‐free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand–foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). Conclusion Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand–foot skin reaction in mCRC patients receiving regorafenib therapy. Micro‐Abstract Regorafenib confers the benefit of longer survival in metastatic colorectal cancer patients. The CCL5/CCR5 pathway modulates endothelial progenitor cell migration and vascular endothelial growth factor A production. Genetic variants of CCL4 and CCL3 may predict outcomes, and the different frequencies of CCL5 homozygote may explain ethnic differences in the development of severe hand–foot skin reactions.

Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer

PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (nu2009=u2009146) and 2 (nu2009=u200970); irinotecan cohorts 1 (nu2009=u2009228), and 2 (nu2009=u2009276); and combination cohort (nu2009=u2009230). Single nucleotide polymorphisms of candidate genes were analyzed by PCR-based direct sequencing. In the oxaliplatin cohort 1, patients carrying any PIN1 rs2233678 C allele had shorter progression-free survival (PFS) and overall survival (OS) than the G/G variant (PFS, 7.4 vs. 15.0 months, hazard ratio [HR] 3.24, Pu2009<u20090.001; OS, 16.9 vs. 31.5 months, HR: 2.38, Pu2009=u20090.003). In contrast, patients with C allele had longer median PFS than patients with G/G (11.9 vs. 9.4 months, HR: 0.64, 95%CI: 0.45–0.91, Pu2009=u20090.009) in the irinotecan cohort 1. No significant differences were observed in the combination cohort. In comparison between the irinotecan cohort 1 and combination cohort, the patients carrying the G/G variant benefit greatly from the combination compared with irinotecan-based regimen (PFS, 11.6 vs. 9.4 months, HR 0.61, 95%CI: 0.47–0.78, Pu2009<u20090.001; OS, 30.6 vs. 24.0 months, HR 0.79, 95%CI: 0.62–1.02, Pu2009=u20090.060), while no significant difference was shown in any C allele. Germline PIN1 polymorphisms may predict clinical outcomes in mCRC patients receiving oxaliplatin-based or irinotecan-based therapy, and identify specific populations favorable to oxaliplatin plus irinotecan combination therapy.