A pharmacogenomic study of docetaxel and gemcitabine for the initial treatment of advanced non-small cell lung cancer
ABSTRACT Pharmacogenomic profiling is an attractive strategy for individualizing chemotherapy. Several genetic polymorphisms predict the survival of patients with non-small cell lung cancer treated with platinum-based chemotherapy. This phase II clinical trial was performed using a non-platinum-based chemotherapy doublet. The impact of previously identified polymorphisms on clinical outcomes was assessed.
Patients with advanced non-small cell lung cancer who had not received previous chemotherapy were treated with docetaxel 40 mg/m2 on days 1 and 8 and gemcitabine 800 mg/m2 days 1 and 8 every 21 days until disease progression or unacceptable toxicity. A pretreatment blood sample was obtained, and genomic DNA was analyzed for polymorphisms in DNA repair and metabolic genes.
Forty-nine patients were enrolled and evaluated for response and survival. The overall radiographic response rate was 38%, and the median survival was 8.6 months. Nonhematologic toxicity was generally mild. Two treatment related deaths occurred: one due to neutropenic sepsis during the first cycle and one due to pulmonary edema after 12 cycles of treatment. Polymorphisms in XPD, XRCC1, and XRCC3 did not significantly predict survival, but trends similar to those reported for platinum-based chemotherapy were observed. The wild-type XPD genotype was associated with prolonged survival and a significantly higher risk of grade 4 neutropenia (p = 0.02).
This regimen of docetaxel and gemcitabine is well tolerated and active for the treatment of advanced non-small cell lung cancer. The impact of XPD polymorphisms on hematologic toxicity is similar to what has been reported for platinum-based chemotherapy.
SourceAvailable from: ncbi.nlm.nih.gov[Show abstract] [Hide abstract]
ABSTRACT: Advanced stage non-small cell lung cancer and head and neck squamous cell carcinoma are both treated with DNA damaging agents including platinum-based compounds and radiation therapy. However, at least one quarter of all tumors are resistant or refractory to these genotoxic agents. Yet the agents are extremely toxic, leading to undesirable side effects with potentially no benefit. Alternative therapies exist, but currently there are no tools to predict whether the first-line genotoxic agents will work in any given patient. To maximize therapeutic success and limit unnecessary toxicity, emerging clinical trials aim to inform personalized treatments tailored to the biology of individual tumors. Worldwide, significant resources have been invested in identifying biomarkers for guiding the treatment of lung and head and neck cancer. DNA repair proteins of the nucleotide excision repair pathway (ERCC1) and of the base excision repair pathway (XRCC1), which are instrumental in clearing DNA damage caused by platinum drugs and radiation, have been extensively studied as potential biomarkers of clinical outcomes in lung and head and neck cancers. The results are complex and contradictory. Here we summarize the current status of single nucleotide polymorphisms, mRNA, and protein expression of ERCC1 and XRCC1 in relation to cancer risk and patient outcomes.Pharmacogenomics and Personalized Medicine 01/2011; 4:47-63. DOI:10.2147/PGPM.S20317
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ABSTRACT: ObjectiveTo investigate whether polymorphisms in ERCC1, XPD, XPG, XRCC1 genes are associated with clinical outcomes in advanced gastric cancer (AGC) patients treated with oxaliplatin-based chemotherapy. MethodsThe genetic polymorphisms in ERCC1, XPD, XPG, XRCC1 were determined in 94 advanced gastric cancer patients treated with oxaliplatin-based chemotherapy, using TaqMan-MGB probes. The clinical response of 60 patients with stage IV disease, time to progression (TTP) and overall survival (OS) of 94 patients were evaluated. ResultsThe overall disease control rate (CR + PR + SD) of the 60 patients in stage IV was 70% (42/60). Patients with XRCC1 399 G/G, XPG 46 C/C genotypes showed enhanced response to the oxaliplatin-based chemotherapy compared to those with other genotypes (P < 0.05). The median OS and TTP of the patients were 5.5 months and 9.0 months, respectively. Among the 4 types of polymorphisms in the study, XRCC1 399 G/A + A/A, XPG 46 C/T + T/T genotypes were regarded to be associated with chemoresistance and poor survival (P < 0.05). Combination analysis of the 2 polymorphisms using the Kaplan-Meier method revealed that the TTP and OS of the patients with a number of risk genotypes were significantly shortened (P < 0.05). No significant association was found between the genotypes of the XPD codon 751, the ERCC1 codon 118 and the clinical outcome (P > 0.05). ConclusionTesting for XRCC1 399, XPG 46 polymorphisms may allow identification of the gastric cancer patients who will benefit from oxaliplatin-based chemotherapy. Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting specific chemotherapy based on pretreatment genotyping represents an innovative strategy that warrants prospective studies.Clinical Oncology and Cancer Research 10/2009; 6(5):328-336. DOI:10.1007/s11805-009-0328-z
Article: Cancer Pharmacogenomics[Show abstract] [Hide abstract]
ABSTRACT: The evolving field of cancer pharmacogenomics uses genetic profiling to predict the response of tumor and normal tissue to therapy. The narrow therapeutic index and heterogeneity of patient responses to chemotherapy and radiotherapy implies that the efficacy of these treatments could, potentially, be significantly enhanced by improving our understanding of the genetic bases for interindividual differences in their effects. The cytotoxicity of both chemotherapy and radiotherapy is to a large extent directly related to their ability to induce DNA damage. The ability of cancer cells to recognize and repair this damage contributes to therapeutic resistance. On the other hand, suboptimal DNA repair in normal tissue may negatively impact on normal tissue tolerance. More than 130 genes have been identified that are associated with human DNA repair, and single nucleotide polymorphisms of several of the DNA repair genes have been described recently. In this article, we present the current evidence implicating variations within DNA repair genes as important predictive and prognostic markers in cancer. We review evidence suggesting DNA repair genetic polymorphisms may significantly influence the clinical response to chemotherapy and radiotherapy, and may influence normal tissue tolerance to cancer treatments.Molecular Diagnosis & Therapy 11/2012; 11(6). DOI:10.1007/BF03256260 · 2.59 Impact Factor