Browsing by Subject "Capecitabine"

Now showing 1 - 4 of 4
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    Correlating Irinotecan and Capecitabine Treatment for Colorectal Cancer to Gene Expression, Polymorphisms, and Clinical Outcomes
    (2011-03-16) Hinkle, David T., IV.; Harrington, Maureen A.; Chiorean, Elena G.; Sanghani, Sonal P.
    Colorectal cancer is the third most common type of cancer and the third most common cause of cancer-related mortality. There are three types of treatment available to patients, either individually or in combination. Treatments are radiation, chemotherapy, and surgery. In a Phase II clinical trial at IUSM, a multimodality approach was chosen. The patients with locally advanced rectal cancer received preoperative treatment with capecitabine and irinotecan (CPT-11) combination followed by chemoradiation with capecitabine and finally surgery to improve response and decrease local recurrence. Irinotecan and Capecitabine are both prodrugs activated in vivo to SN-38 and 5-FU, respectively. Identification of the molecular markers for 5-FU and Irinotecan efficacy and toxicity is important for the development of more efficient and less toxic treatment strategies for patients with colorectal cancer. The goal of this study was to determine the expression levels of the genes involved in activation and metabolism of capecitabine and irinotecan in pre and post treatment specimens from these patients. The genes quantitated by real-time PCR were carboxylesterase 1 and 2 (CES1 and CES2), thymidylate synthase (TS), β-glucoronidase (β-GUS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and topoisomerase I (Topo I). The UGT1A1*28 polymorphism in UDP glucuronosyltransferase 1 is associated with SN-38 toxicity. Therefore, the UGT1A1*28 polymorphism status in patients was determined by PCR-sequencing. Correlative analysis of gene expression and UGT1A1*28 mutation with clinical outcome in this Phase II study was completed.
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    Human carboxylesterase 2 splice variants: expression, activity, and role in the metabolism of irinotecan and capecitabine
    (2009-02) Schiel, Marissa Ann; Bosron, William F.; Chiorean, E. Gabriela; Flockhart, David A.; Harrington, Maureen A.; Sanghani, Sonal P.
    Carboxylesterases (CES) are enzymes that metabolize a wide variety of compounds including esters, thioesters, carbamates, and amides. In humans there are three known carboxylesterase genes CES1, CES2, and CES3. Irinotecan (CPT-11) and capecitabine are important chemotherapeutic prodrugs that are used for the treatment of colorectal cancer. Of the three CES isoenzymes, CES2 has the highest catalytic efficiency for irinotecan activation. There is large inter-individual variation in response to treatment with irinotecan. Life-threatening late-onset diarrhea has been reported in approximately 13% of patients receiving irinotecan. Several studies have reported single nucleotide polymorphisms (SNPs) for the CES2 gene. However, there has been no consensus on the effect of different CES2 SNPs and their relationship to CES2 RNA expression or irinotecan hydrolase activity. Three CES2 mRNA transcripts of approximately 2kb,3kb, and 4kb have been identified by multi-tissue northern analysis. The expressed sequence tag (EST) database indicates that CES2 undergoes several splicing events that could generate up to six potential proteins. Four of the proteins CES2, CES2458-473, CES2+64, CES21-93 were studied to characterize their expression and activity. Multi-tissue northern analysis revealed that CES2+64 corresponds to the 4kb and 3kb transcripts while CES21-93 is located only in the 4 kb transcript. CES2458-473 is an inactive splice variant that accounts for approximately 6% of the CES2 transcripts in normal and tumor colon tissue. There is large inter-individual variation in CES2 expression in both tumor and normal colon samples. Characterization of CES2+64 identified the protein as normal CES2 indicating that the signal peptide is recognized in spite of the additional 64 amino acids at the N-terminus. Sub-cellular localization studies revealed that CES2 and CES2+64 localize to the ER, and CES21-93 localizes to the cytoplasm. To date CES2 SNP data has not provided any explanation for the high inter-individual variability in response to irinotecan treatment. Multi-tissue northern blots indicate that CES2 is expressed in a tissue specific manner. We have identified the CES2 variants which correspond to each mRNA transcript. This information will be critical to defining the role of CES2 variants in the different tissues.
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    Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study
    (Springer Nature, 2019-07) Bang, Yung-Jue; Kang, Yoon-Koo; Catenacci, Daniel V.; Muro, Kei; Fuchs, Charles S.; Geva, Ravit; Hara, Hiroki; Golan, Talia; Garrido, Marcelo; Jalal, Shadia I.; Borg, Christophe; Doi, Toshihiko; Yoon, Harry H.; Savage, Mary J.; Wang, Jiangdian; Dalal, Rita P.; Shah, Sukrut; Wainberg, Zev A.; Chung, Hyun Cheol; Medicine, School of Medicine
    BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. METHODS: Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma.
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    Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131
    (American Society of Clinical Oncology, 2021) Mayer, Ingrid A.; Zhao, Fengmin; Arteaga, Carlos L.; Symmans, William F.; Park, Ben H.; Burnette, Brian L.; Tevaarwerk, Amye J.; Garcia, Sofia F.; Smith, Karen L.; Makower, Della F.; Block, Margaret; Morley, Kimberly A.; Jani, Chirag R.; Mescher, Craig; Dewani, Shabana J.; Tawfik, Bernard; Flaum, Lisa E.; Mayer, Erica L.; Sikov, William M.; Rodler, Eve T.; Wagner, Lynne I.; DeMichele, Angela M.; Sparano, Joseph A.; Wolff, Antonio C.; Miller, Kathy D.; Medicine, School of Medicine
    Purpose: Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine. Patients and methods: Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine. Results: Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum. Conclusion: Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.