Gender-specific genomic profiling in metastatic colorectal cancer patients treated with 5-fluorouracil and oxaliplatin.

Aims: Survival and response rates in metastatic colorectal cancer remain poor, despite advances in drug development. There is increasing evidence to suggest that gender-specific differences may contribute to poor clinical outcome. We tested the hypothesis that genomic profiling of metastatic colorectal cancer is dependent on gender.

The colorectal cancer disease-specific transcriptome may facilitate the discovery of more biologically and clinically relevant information.

Background: To date, there are no clinically reliable predictive markers of response to the current treatment regimens for advanced colorectal cancer. The aim of the current study was to compare and assess the power of transcriptional profiling using a generic microarray and a disease-specific transcriptome-based microarray. We also examined the biological and clinical relevance of the disease-specific transcriptome.

Germline polymorphisms in genes involved in the CD44 signaling pathway are associated with clinical outcome in localized gastric adenocarcinoma.

The cluster of differentiation 44 (CD44) signaling pathway is crucial in cancer-cell growth, invasion, proliferation and metastasis. CD44 is a transmembrane receptor for hyaluronan and osteopontin, and has recently attracted attention as a gastric cancer stem cell marker. Previous studies showed that polymorphisms in the CD44 gene can influence both human cancer survival and determine cellular response to cytotoxic chemotherapeutics.

Molecular predictors of combination targeted therapies (cetuximab, bevacizumab) in irinotecan-refractory colorectal cancer (BOND-2 study).

Background: To test whether intratumoral gene expression levels and germline polymorphisms predict clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab and bevacizumab plus irinotecan (CBI) vs. cetuximab and bevacizumab (CB)(BOND2).

Patients And Methods: Genomic DNA was extracted for genotyping from 65 patients (31: CBI arm and 34: CB arm).

Phase II trial of bryostatin-1 in combination with cisplatin in patients with recurrent or persistent epithelial ovarian cancer: a California cancer consortium study.

Background: The California Cancer Consortium has performed a Phase II trial of infusional bryostatin, a protein kinase C inhibitor isolated from the marine invertebrate bryozoan, Bugula Neritina, a member of the phylum Ectoprocta, in combination with cisplatin, in patients (pts) with recurrent platinum-sensitive or resistant ovarian cancer (OC).

Methods: Pts received bryostatin 45 mcg/m(2) as a 72 h continuous infusion followed by cisplatin 50 mg/m(2). Cycles were repeated every 3 weeks.

Germline polymorphisms in genes involved in the IGF1 pathway predict efficacy of cetuximab in wild-type KRAS mCRC patients.

Purpose: The insulin-like growth factor 1 (IGF1) signaling pathway is an important growth-regulatory pathway, which plays a crucial role in colorectal cancer (CRC) proliferation, differentiation, migration, angiogenesis, and apoptosis. Previous studies showed that hyperactivation of the IGF1 receptor (IGF1R) may result in resistance to anti-epidermal growth factor receptor-targeted treatment. We tested whether germline variations within the IGF1 pathway are associated with clinical outcome in wild-type (wt) KRAS drug-refractory metastatic CRC (mCRC) patients who were treated with cetuximab monotherapy (IMC-0144).

Molecular response prediction in multimodality treatment for adenocarcinoma of the esophagus and esophagogastric junction.

Cancers arising from the esophagus are becoming more common in the United States and Europe. In 2009, an estimate of 14,530 new cases will be diagnosed and more than 90% will die of their disease. Esophageal cancer is currently the most rapidly increasing cancer in the western world and is coinciding with a shift in histological type and primary tumor location.

Mucinous adenocarcinomas with intra-abdominal dissemination: a review of current therapy.

Peritoneal carcinomatosis has been considered a terminal disease with a median survival time of 5.2-12.6 months.

Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models.

Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, is known to possess tumorigenic and proangiogenic properties. Overexpression of IL-8 has been detected in many human tumors, including colorectal cancer (CRC), and is associated with poor prognosis. The goal of our study was to determine the role of IL-8 overexpression in CRC cells in vitro and in vivo.

Cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma: a phase II Southwest Oncology Group Study (S0415).

Introduction: Esophageal adenocarcinomas commonly express the epidermal growth factor receptor. This trial assessed the 6-month overall survival probability in metastatic esophageal cancer patients treated with cetuximab as second-line therapy.

Methods: This was a multicenter, open-label phase II study of single-agent cetuximab for metastatic esophageal adenocarcinoma patients who failed one prior chemotherapy regimen.

Integrating biomarkers into clinical decision making for colorectal cancer.

The advent of pharmacogenetics and its underlying concept that disparities in drug metabolism, efficacy, and toxicity are determined by the genetic makeup of an individual has birthed the concept and promise of 'tailored medicine.' One such facet of medicine that serves to benefit greatly from this tailored approach is the implementation of chemotherapy in cancer treatment. The past decade has witnessed significant advances in the treatment of colorectal cancer (CRC); however, tumor drug resistance remains a major obstacle in CRC treatment, and many patients do not receive any clinical benefit from chemotherapy.

A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy.

Purpose: recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3' untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy.

Gender-related survival differences associated with polymorphic variants of estrogen receptor-β (ERβ) in patients with metastatic colon cancer.

Estrogen replacement therapy in women has shown a protective effect on the development of colonic carcinomas. Gender-related differences in the development of colonic carcinomas have also been reported. Estrogen receptor-β (ERβ) is expressed in colon carcinomas and has shown prognostic value in colon cancer patients.

Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009.

The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation.

Molecular markers in the treatment of metastatic colorectal cancer.

Although significant progress has been made in colorectal cancer (CRC) treatment within the last decade with the approval of multiple new agents, the prognosis for patients with metastatic CRC remains poor with 5-year survival rates of approximately 8%. Resistance to chemotherapy remains a major obstacle in effective CRC treatment and many patients do not receive any clinical benefit from chemotherapy. In addition, other patients will experience adverse reactions to treatment resulting in dose modifications or treatment withdrawal, which can severely reduce treatment efficacy.

Vascular endothelial growth factor and epidermal growth factor signaling pathways as therapeutic targets for colorectal cancer.

Treatment of colorectal cancer (CRC) has developed considerably over the past decade, especially in the areas of targeted therapeutics and biomarker development. Multiple cellular pathways influence the growth and metastatic potential of CRC. Targeted therapies have been designed to interfere with specific molecular events in pathways that mediate tumor growth and progression.

Pharmacogenetic profiling of Aurora kinase B is associated with overall survival in metastatic colorectal cancer.

Aurora kinases are conserved eukaryotic serine-threonine kinases, which serve as key regulators of mammalian mitosis. Several studies revealed a distinct correlation between inaccurate chromosome segregation, leading to chromosomal number instability, cancer progression and poor outcome. The aim of this study was to investigate the correlation of Aurora kinases A (AURKA) and B (AURKB) with overall survival (OS) by quantifying gene expression analysis and evaluation of single-nucleotide polymorphisms (SNPs) in human colorectal cancer samples and assessing the associations with clinicopathological features.

Molecular predictive and prognostic markers in colon cancer.

Colorectal cancer remains one of the major cancer related death despite progress in the cytotoxic treatment of colorectal cancer (CRC) over the past decade. The introduction of targeted agents has improved the progression free and overall survival of metastatic disease. However, 40-50% of patients do not experience beneficial effects and it remains a challenge to select patients likely to respond to therapy.

Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery.

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting.

Colorectal cancer.

Substantial progress has been made in colorectal cancer in the past decade. Screening, used to identify individuals at an early stage, has improved outcome. There is greater understanding of the genetic basis of inherited colorectal cancer and identification of patients at risk.

Phase I clinical trial of pegylated liposomal Doxorubicin and docetaxel in patients with advanced solid tumors.

Objective: The primary objective of this study was to determine the maximum tolerated dose (MTD) of pegylated liposomal doxorubicin (PLD) and docetaxel (T) administered in 4 week cycles in patients with advanced solid tumors.

Patients And Methods: Patients were treated with intravenous PLD on day 1 and T on days 1, 8, and 15. Once the MTD was reached the schedule of PLD was changed to days 1 and 15 to explore an alternative and potentially more manageable dosing schedule.

EGFR signaling and drug discovery.

Dysregulation of human epidermal growth factor receptor (ErbB/HER) pathways by over-expression or constitutive activation can promote tumor processes including angiogenesis and metastasis and is associated with poor prognosis in many human malignancies. In addition to cancer, ErbB signaling has also been implicated in cardiovascular and neurodegenerative diseases. Conversely, inhibition of ErbB pathways with targeted agents, such as monoclonal antibodies (MoAbs) or tyrosine kinase inhibitors (TKIs), blocks cell cycle progression, inhibits the production of pro-angiogenic factors and induces apoptosis in numerous in vitro and xenograft models.

Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus.

Objective: The aim of this study was to determine whether the risk of systemic disease after esophagectomy could be predicted by angiogenesis-related gene polymorphisms.

Summary Background Data: Systemic tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis will help to better define tumor stage, indicate disease progression, identify novel therapeutic targets, and monitor response to therapy.

A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy.

Purpose: We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

Methods: Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily.