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Susan Groshen

Publications and source records attributed to Susan Groshen.

At least 19 recordsLinked to original sources
PubMed2006

GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer.

The discovery of predictive factors for chemoresistance is critical for improving adjuvant therapy for cancer patients. The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of the unfolded protein response (UPR), is induced in the tumor microenvironment. In vitro studies suggest that GRP78 confers chemoresistance to topoisomerase inhibitors, such as Adriamycin (doxorubicin). Here, we report on a retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy. Archival tumor specimens were available for analysis and the relationship of GRP78 expression level to "time to recurrence" (TTR), used as a surrogate marker for drug resistance, was examined. Our data show that 67% of the study subjects expressed high level of GRP78 in their tumors before the initiation of chemotherapy and suggest an association between GRP78 positivity and shorter TTR [hazard ratio (HR), 1.78; P = 0.16]. Interestingly, subgroup analysis reveals that the HR for the GRP78-positive group increased significantly among patients who did not receive further taxane treatment (HR, 3.00; P = 0.022) and among mastectomy patients (HR, 3.33; P = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; P = 0.010). The use of GRP78 as a predictor for chemoresponsiveness and the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant larger studies.

Antineoplastic Agents↗
PubMed2006

Detection of occult lymph node metastases in locally advanced node-negative prostate cancer.

PURPOSE: The purpose of this study was to determine the incidence and clinical significance of occult metastases in the lymph nodes of patients with prostate cancer originally considered node negative by routine histologic evaluation. METHODS: Two hundred seventy four patients with pT3 prostate carcinoma treated by radical prostatectomy and bilateral lymph node dissection were included in this study. One hundred eighty patients were staged node negative (N0), while 94 patients were lymph node positive (N+), based on routine histologic evaluation. All lymph nodes from the 180 N0 patients were evaluated for occult metastases by immunohistochemistry using antibodies to cytokeratins and, if positive, prostate-specific antigen. Recurrence and overall survival were compared among patients with occult tumor cells (OLN+), with patients whose lymph nodes remained negative (OLN-), and with the 94 N+ patients. RESULTS: A total of 3,914 lymph nodes were evaluated from 180 N0 patients (average, 21.7 lymph nodes per patient). Occult tumor cells were found in 24 of 180 patients (13.3%). The presence of OLN+ was significantly associated with increased recurrence and decreased survival compared with OLN- patients (P < .001 and P = .019, respectively; relative risk of recurrence, 2.27; relative risk of death 2.07, respectively). The presence of occult lymph node metastases was an independent predictor of recurrence and death in a multivariable analysis. The outcome for patients with OLN+ disease was similar to that for patients with N+ disease. CONCLUSION: The detection of occult lymph node metastases in patients with pT3N0 prostate cancer identifies those with significantly increased risk of prostate cancer recurrence and death.

Aged↗
PubMed2006

Prognostic significance of neuroendocrine expression in lymph node-positive prostate cancer.

OBJECTIVES: To evaluate the expression of chromogranin A, a marker for neuroendocrine (NE) differentiation, in patients with lymph node-positive prostate cancer to determine its prognostic significance. NE cells are involved in cellular growth and differentiation in both normal and pathologic conditions of the prostate. METHODS: We reviewed the data of 140 patients with lymph node-positive prostate adenocarcinoma treated with radical prostatectomy and pelvic lymphadenectomy. The median follow-up was 10.9 years (range 0.8 to 19.7). Immunohistochemical staining for chromogranin A was evaluated in areas of benign epithelium, primary prostate cancer, and lymph node metastasis. The association between chromogranin A expression and the clinical and pathologic factors (preoperative serum prostate-specific antigen and prostatectomy Gleason score and stage) and clinical outcomes, including overall and recurrence-free survival, was evaluated. RESULTS: Staining was positive in 86% of benign areas, 61% of primary cancer specimens, and 12% of lymph node deposits. The preoperative serum prostate-specific antigen level and pathologic stage and grade of the primary tumor did not show any statistically significant correlation with NE staining in any of the areas. Only NE expression in the primary tumor was associated with clinical recurrence, with a 10-year recurrence-free survival rate for those with less than 5% staining of 67% compared with 35% for those with 5% staining or greater (P = 0.03). Furthermore, after adjusting for age, greater NE expression in the primary tumor (relative risk 2.15, P = 0.02) and lymph node deposit (relative risk 2.03, P = 0.03) was associated with poorer overall survival. CONCLUSIONS: NE expression in the primary tumor and lymph node metastasis of patients with node-positive prostate cancer may provide additional prognostic stratification.

Adenocarcinoma↗
PubMed2006

Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis.

BACKGROUND: The purpose of the current study was to determine the toxicity and response of a fixed dose intracerebrospinal fluid (CSF) etoposide in the treatment of patients with newly diagnosed neoplastic meningitis (NM). NM reportedly occurs in 1% to 5% of patients with known cancer. Currently available treatment options are limited and provide only modest benefit. METHODS: Twenty-seven patients (median age, 55 yrs) with clinically and cytologically documented NM received intra-CSF etoposide. Tumor histologies included lung (8 patients), breast (5 patients), primary brain tumor (4 patients), non-Hodgkin lymphoma (4 patients), melanoma (4 patients), colon (1 patient), and prostate (1 patient). Concurrent involved-field radiotherapy (19 of 27 patients) or systemic chemotherapy (17 of 27 patients) was administered based on clinical indications. Etoposide was administered at a fixed dose (0.5 mg every day given 5 days per week every other week for 8 weeks [induction]). Patients were evaluated by CSF cytology and neurologic examination at the conclusion of induction therapy. Responding patients continued to receive etoposide (5 consecutive days every 4 weeks) with monthly evaluations. RESULTS: Seven of 27 patients (26%) treated with etoposide had a cytologic response and either stable or improved neurologic status at the conclusion of induction. Eight patients (30%) developed disease progression during induction therapy and did not complete the 8-week induction course of therapy. At the conclusion of induction therapy, 12 patients (44%) had persistently positive CSF cytology, although they were clinically stable. In responding patients, time to neurologic disease progression ranged from 8 weeks to 40 weeks (median, 20 wks). Toxicity manifested as transient chemical arachnoiditis (5 of 27 patients; 13% of all treatment cycles). The 6-month neurologic disease progression-free survival was 11%. CONCLUSIONS: Etoposide appears to have modest activity against NM and easily managed toxicity.

Adult↗
PubMed2006

Salvage chemotherapy with CPT-11 for recurrent meningioma.

BACKGROUND: A prospective Phase II study of irinotecan (CPT-11) in adult patients with recurrent surgery and radiotherapy-refractory WHO Grade I meningioma. METHODS: Sixteen patients (5 men; 11 women) ages 48-70 years (median 62.5), with recurrent meningioma were treated. All patients had previously been treated with surgery (complete in 4; partial in 9; biopsy in 3) and involved-field radiotherapy (median dose 54 Gy; 12 following first surgery and 4 following second surgery). Additionally, eight patients underwent re-operation (complete in 2; partial in 6) and eight patients were treated with salvage stereotactic radiosurgery. No patient was treated with prior chemotherapy. CPT-11 was administered intravenously every 3 weeks (350 mg/m2/day in patients on non-enzyme inducing anticonvulsants [NEIAED]; 600 mg/m2/day in patients on enzyme-inducing anticonvulsants [EIAED]) for 9 weeks (operationally defined as a single cycle). Neurological and neuroradiographic evaluation were performed every 10 weeks. RESULTS: All patients were evaluable. A median of two cycles of CPT-11 (range 1-4) was administered. CPT-11 related-toxicity (> or = grade 3) included diarrhea (6 occurrences, 19% all cycles administered), granulocytopenia (6, 19%), leukopenia (5, 16%), thrombocytopenia (3, 10%) and anemia (3, 10%). Four patients required transfusion (3 RBC and 1 platelet). One patient developed neutropenic fever without bacteriologic confirmation. No treatment-related deaths occurred. No patient demonstrated a neuroradiographic complete or partial response (PR), 13 patients (81%) demonstrated stable disease but disease progressed after 2 cycles of CPT-11, and 3 patients (19%) had progressive disease (PD) following a single cycle of CPT-11. Time to tumor progression ranged from 2.5 to 5.0 months (median 5.0 months). Survival ranged from 4 to months (median 7.5 months). CONCLUSIONS: The primary objective was to estimate the 6-month progression-free survival (PFS) after study entry. As no patient demonstrated PFS at 6-months, the study was stopped prematurely as specified by study design. Using CPT-11 in this moderately toxic dose schedule failed to demonstrate efficacy in this cohort of adult patients with recurrent surgery and radiotherapy-refractory meningioma.

Aged↗
PubMed2006

Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study.

PURPOSE: To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma. PATIENTS AND METHODS: Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-MIBG was administered on day -21, CEM was administered on days -7 to -4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. (131)I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR). RESULTS: The MTD for patients with normal GFR (> or = 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 +/- 0.10 and 0.58 +/- 0.10, respectively. CONCLUSION: 131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.

3-Iodobenzylguanidine↗
PubMed2006

Salvage chemotherapy with cyclophosphamide for recurrent temozolomide-refractory anaplastic astrocytoma.

BACKGROUND: A prospective Phase II study of cyclophosphamide (CYC) was conducted in adult patients with recurrent temozolomide-refractory anaplastic astrocytoma (AA) with a primary objective of evaluating 6-month progression-free survival (PFS). METHODS: Forty patients (28 men, 12 women) ages 26-57 years (median, 43 yrs) with neuroradiographically recurrent AA were treated. All patients had previously been treated with surgery and involved-field radiotherapy. Additionally, all patients were treated with temozolomide (TMZ) chemotherapy after radiotherapy. All patients were treated at recurrence with CYC administered intravenously on 2 consecutive days (750 mg/m2/day) every 4 weeks (operationally defined as a single cycle). Neurologic and neuroradiographic evaluation were performed every 8 weeks. RESULTS: All patients were evaluable. A total of 215 cycles of CYC (median, 4 cycles; range 2-12 cycles) was administered. CYC-related toxicity included alopecia (all patients, 100%), anemia (5, 12.5%), thrombocytopenia (6, 15%), and neutropenia (8, 20%). Four (10%) patients required transfusion. Nine patients (22.5%) (95% confidence interval [95% CI], 11%-39%) demonstrated a neuroradiographic partial response, 16 patients (40.0%) (95% CI, 25%-57%) demonstrated stable disease, and 15 patients (37.5%) (95% CI, 23%-54%) had progressive disease after 2 cycles of CYC. Time to tumor progression ranged from 2-19 months (median, 4 mos; 95% CI, 2-6 mos). Survival ranged from 2-26 months (median, 8 mos; 95% CI, 6-10 mos). The 6-month and 12-month PFS was 30% and 8%, respectively. CONCLUSIONS: CYC demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent anaplastic astrocytoma, all of whom had failed prior TMZ chemotherapy.

Adult↗
PubMed2006

Comparisons of PCR-based genome amplification systems using CpG island microarrays.

The characterization of complex DNA libraries by high-throughput sequencing technologies provides a powerful approach toward finding mutations and genetic variation in the human genome. However, the value of these analyses is highly dependent upon the quality of the DNA libraries themselves. For example, the sequence composition of libraries made using PCR-based procedures can be skewed due to biases in the amplification efficiency of individual library members. Here, we used CpG island microarrays to evaluate the biases incurred in PCR-based genome amplification using three different DNA polymerase mixtures designed to efficiently amplify problematic sequence tracts. Based on hybridization properties of dye-labeled DNA libraries to these microarrays, we quantified the overall and specific trends in the PCR efficiency of more than 1,400 sequences with high GC-content, which generally amplify with low efficiency using conventional PCR protocols. Overall, all three DNA polymerase mixtures produced libraries that show substantial increases in the representation of CpG island segments that poorly amplify with Taq DNA polymerase. However, the effects of these DNA polymerases were quite specific since they did not alter the relative representation of segments that efficiently amplify with Taq DNA polymerase. Furthermore, we demonstrate that DNA microarrays provide a robust platform for rapidly evaluating the ability of different PCR systems to amplify difficult genomic regions targeted for mutational, resequencing, and genotyping analyses.

Base Composition↗
PubMed2006

Superficial (pT2a) and deep (pT2b) muscle invasion in pathological staging of bladder cancer following radical cystectomy.

PURPOSE: We compared and evaluated clinical outcomes in patients with pathological superficial (pT2a) and deep (pT2b) invasion of bladder muscle with transitional cell carcinoma following radical cystectomy and urinary diversion. MATERIALS AND METHODS: From 1971 to 2001, 311 of 1,359 patients (23%), including 244 males (78%) and 67 females, were found to have pathological muscle invasive (pT2) bladder cancer following radical cystectomy. Of this group 147 patients (47%) had pT2a (superficial) and 164 (53%) had pT2b (deep) muscle invasive tumors. Overall 242 patients had no evidence of lymph node metastasis, including 127 with pT2a (86%) and 115 with pT2b (70%). A total of 69 patients (22%) had lymph node involvement, including 20 with pT2a (14%) and 49 with pT2b (30%). At a median followup of 14.3 years (range 0 to 30.1) clinical outcomes were determined, including recurrence-free and overall survival, and local vs distant recurrence. RESULTS: In the 311 patients with pT2 tumors 10-year recurrence-free and overall survival rates were 72% and 47%, respectively. There was a significantly higher risk of node positive disease with pT2b vs pT2a tumors (30% vs 14%, p <0.001). No significant difference was observed in 10-year recurrence-free survival in patients with pT2a node negative vs pT2b node negative tumors (84% vs 72%, p = 0.091). When comparing pT2a node positive vs pT2b node positive tumors, no significant difference was observed in 10-year recurrence-free survival (50% vs 48%, p = 0.84). Recurrence-free survival was significantly higher in patients with pT2 lymph node negative tumors than in those with pT2 lymph node positive tumors (79% vs 49%, p <0.001). Furthermore, these differences remained significant when stratified by pT2a and pT2b node negative vs positive disease. Local pelvic recurrence developed in 10 of 311 patients (3%) with pT2 disease, while 69 (22%) had distant metastatic disease. In patients with recurrence the local or distant recurrence site was not associated with tumor stage (pT2a vs pT2b p = 0.24) or lymph node status (node negative vs positive p = 0.37). CONCLUSIONS: In muscle invasive (pT2) bladder cancer treated with radical cystectomy there is a higher risk of lymph node positive disease in deep muscle (pT2b) vs superficial (pT2a) invasion. However, no apparent difference was observed in recurrence-free survival between pT2a (superficial) vs pT2b (deep) muscle invasive tumors when controlling for lymph node status. Recurrence-free survival is significantly improved in patients with pT2 lymph node negative tumors compared to survival in those with pT2 lymph node positive tumors. Patients with muscle invasive (pT2), lymph node negative tumors have excellent clinical outcomes following cystectomy, while those with muscle invasive (pT2), lymph node positive tumors have higher recurrence rates and should be considered for adjuvant treatment protocols.

Adult↗
PubMed2006

Salvage radical prostatectomy: quality of life outcomes and long-term oncological control of radiorecurrent prostate cancer.

PURPOSE: We review our 20-year experience with salvage radical prostatectomy to determine prognostic variables predictive of oncological control of radiorecurrent prostate cancer. Using a standardized questionnaire we also evaluate outcome data regarding the long-term sexual and urinary effects of salvage radical prostatectomy. MATERIALS AND METHODS: Between 1983 and 2002 salvage radical prostatectomy was performed in 51 patients with locally recurrent prostate cancer following definitive radiotherapy. Clinical information was obtained from a prospective database. Quality of life data were collected using the UCLA Prostate Cancer Index, a validated, patient administered instrument. RESULTS: At 5 years 47% of patients were progression-free without androgen deprivation therapy. Among patients with pT2 disease 100% were progression-free at 5 years, compared with 35% of patients with pT3N0 disease or higher and 0% of patients with node positive (pTxN+) disease (p < 0.001). Preoperative PSA 5.0 ng/ml or less was predictive of organ confined disease, and strongly associated with prolonged progression-free and overall survival (p < 0.001 and 0.01, respectively). Mean urinary function scores for patients with or without an artificial urinary sphincter compared favorably with scores reported after standard, nonsalvage prostatectomy. Sexual dysfunction was nearly uniform in patients undergoing standard salvage radical prostatectomy but implantation of a penile prosthesis was associated with a clinically significant improvement in sexual function. CONCLUSIONS: When initiated early in the course of recurrent disease, salvage radical prostatectomy provides excellent oncological control of radiorecurrent prostate cancer without the need for androgen ablation. Implantation of an artificial urinary sphincter and inflatable penile prosthesis devices in patients with postoperative urinary incontinence or erectile dysfunction results in significantly improved quality of life parameters.

Aged↗
PubMed2006

Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer.

PURPOSE: Vascular endothelial growth factor has a critical role in maintaining tumor microvasculature and, as such, is an attractive target for anti-angiogenic therapy. Aberrant expression of VEGF receptors, especially VEGFR2, on epithelial tumor cells allows VEGF to stimulate growth and migration of tumor cells in an autocrine and/or paracrine manner. Therefore, we studied the expression of VEGF and VEGFR2 in bladder cancer, and the relationship to disease characteristics. MATERIALS AND METHODS: Expression of VEGF and VEGFR2 was studied in a cohort of 72 patients with transitional cell cancer of the bladder. Tumor tissues from all patients were analyzed by immunohistochemistry and examined by a pathologist blinded to patient outcome. Patient demographics and disease outcome were correlated with expression of these markers. Bladder cancer cell lines that express VEGFR2 were studied in vitro and in vivo to establish the significance of VEGF/VEGFR2 signaling. RESULTS: Expression of VEGF and VEGFR2 was observed in 58% and 50% of urothelial tumor cells, respectively. VEGF expression failed to correlate with clinical variables. However, VEGFR2 expression correlated with disease stage (coefficient 0.23, p = 0.05). In addition, VEGFR2 expression increased with tumor invasion into the muscle (p <0.01). Experiments with VEGFR2 positive bladder cancer cell lines in vitro demonstrated increased invasion in response to VEGF. In addition, VEGF inhibition augmented the effect of docetaxel in a murine xenograft model of bladder cancer with a significant inhibition in proliferative index and microvascular density, and induction of apoptosis. CONCLUSIONS: Increased VEGFR2 expression correlates with several features that predict progression of urothelial cancer, including disease stage and invasive phenotype. VEGF targeted therapy may enhance the efficacy of standard therapy for bladder cancer.

Adult↗
PubMed2006

Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab.

The study aimed to investigate whether polymorphisms in genes of the EGFR signaling pathway are associated with clinical outcome in advanced colorectal cancer (CRC) patients treated with single-agent Cetuximab. Polymorphisms of interest in the EGFR pathway include: cyclin D1 (CCND1) A870G, cyclooxygenase 2 (Cox-2) G-765C, epidermal growth factor (EGF) A61G, epidermal growth factor receptor (EGFR) codon R497 K, EGFR CA dinucleotide repeat in intron 1, interleukin (IL)-8 T-251A and vascular endothelial growth factor (VEGF) C936 T gene polymorphisms. Thirty-nine metastatic CRC patients were enrolled in the IMCL-0144 trial and treated with single-agent Cetuximab. Using the polymerase chain reaction-restriction fragment length polymorphism method, gene polymorphisms of CCND1, COX-2, EGF, EGFR, IL-8 and VEGF were assessed from genomic DNA extracted from blood samples. A significant association was found between the CCND1 A870G polymorphism and overall survival in our 39 CRC subjects. Patients with the AA homozygous genotype survived for a median of 2.3 months [95% confidence interval (CI)=2.1-5.7], whereas those with any G allele (AG, GG genotype) survived for a median of 8.7 months (95% CI=4.4-13.5) (P=0.019, log-rank test). When we analysed the cyclin D1 and EGF polymorphisms together, patients with favourable genotypes (EGF any A allele and CCND1 any G allele) showed a median survival time of 12 months (95% CI=4.8-15.2), whereas patients with any two unfavourable genotypes (EGF GG or CCND1 AA) showed a median survived time of 4.4 months (95% CI=2.1-5.7) (P=0.004, log-rank test). The findings of this pilot study suggest that the cyclin D1 A870G and the EGF A61G polymorphisms may be useful molecular markers for predicting clinical outcome in CRC patients treated with single-agent Cetuximab.

Adult↗
PubMed2006

Gene expression in tumor-adjacent normal tissue is associated with recurrence in patients with rectal cancer treated with adjuvant chemoradiation.

Recurrence is a significant clinical problem for patients with rectal cancer treated with adjuvant chemoradiation. Previous studies have suggested that determining intratumoral gene expression of key genes may be helpful in predicting clinical outcome of patients with gastrointestinal malignancies undergoing chemotherapy. The role of molecular predictors for prediction of recurrence in the setting of adjuvant chemoradiotherapy is not well established. The present study was designed to identify a genetic profile that would be associated with recurrence in patients with rectal cancer treated with adjuvant chemoradiation therapy. A retrospective study with a longitudinal cohort and a cross-sectional cohort of 67 patients with locally advanced rectal cancer who underwent cancer resection, followed by 5-fluorouracil (5-FU) plus pelvic radiation was conducted. Total RNA was extracted from formalin-fixed, paraffin-embedded, laser-captured-microdissected tissue. We determined mRNA levels of genes involved in the 5-FU pathway (thymidylate synthase, dihydropyrimidine dehydrogenase), DNA-repair (excision-repair cross-complementing factor 1, Rad51), angiogenesis/radiation sensitivity [vascular endothelial growth factor (VEGF)] and radio-sensitivity [epidermal growth factor receptor (EGFR)] in tumor tissue and tumor-adjacent normal tissue by quantitative reverse transcriptase-polymerase chain reaction. In univariate analysis, only intratumoral gene expression level of VEGF (P = 0.055) was associated with recurrence, whereas elevated mRNA expression levels of thymidylate synthase (P = 0.008), VEGF (P = 0.023) and EGFR (P = 0.004) in tumor-adjacent normal tissue were significantly associated with recurrence. Multivariate analysis using recursive partitioning indicated that distinct groups of recurrence could be defined by elevated mRNA expression levels of VEGF, EGFR in tumor-adjacent normal tissue, and Rad51 in tumor tissue. These data suggest that the genetic profile of the tumor-adjacent normal tissue may be associated with treatment failure, indicating that tumor microenvironment may be more important in the development of recurrence of rectal tumors than formerly expected.

Adult↗
PubMed2006

Genomic profiling associated with recurrence in patients with rectal cancer treated with chemoradiation.

PURPOSE: Stage II and III adenocarcinoma of the rectum has an overall 5-year survival rate of approximately 50%, and tumor recurrence remains a major problem despite an improvement in local control through chemotherapy and radiation. The efficacy of chemoradiation therapy may be significantly compromised as a result of interindividual variations in clinical response and host toxicity. Therefore, it is imperative to identify those patients who will benefit from chemoradiation therapy and those who will develop recurrent disease. In this study, we tested whether a specific pattern of 21 polymorphisms in 18 genes involved in the critical pathways of cancer progression (i.e., drug metabolism, tumor microenvironment, cell cycle regulation, and DNA repair) will predict the risk of tumor recurrence in rectal cancer patients treated with chemoradiation. PATIENTS AND METHODS: A total of 90 patients with Stage II or III rectal cancer treated with chemoradiation were genotyped using polymerase chain reaction (PCR)-based techniques for 21 polymorphisms. RESULTS: A polymorphism in interleukin (IL)-8 was individually associated with risk of recurrence. Classification and regression tree analysis of all polymorphisms and clinical variables developed a risk tree including the following variables: node status, IL-8, intracellular adhesion molecule-1, transforming growth factor-beta, and fibroblast growth factor receptor 4. CONCLUSION: Genomic profiling may help to identify patients who are at high risk for developing tumor recurrence, and those who are more likely to benefit from chemoradiation therapy. A larger prospective study is needed to validate these preliminary data using germline polymorphisms on tumor recurrences in rectal cancer patients treated with chemoradiation.

Antineoplastic Agents↗
PubMed2005

Molecular determinants of cetuximab efficacy.

PURPOSE: To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. RESULTS: There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. CONCLUSION: This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.

Adult↗
PubMed2005

Comparisons of substitution, insertion and deletion probes for resequencing and mutational analysis using oligonucleotide microarrays.

Although oligonucleotide probes complementary to single nucleotide substitutions are commonly used in microarray-based screens for genetic variation, little is known about the hybridization properties of probes complementary to small insertions and deletions. It is necessary to define the hybridization properties of these latter probes in order to improve the specificity and sensitivity of oligonucleotide microarray-based mutational analysis of disease-related genes. Here, we compare and contrast the hybridization properties of oligonucleotide microarrays consisting of 25mer probes complementary to all possible single nucleotide substitutions and insertions, and one and two base deletions in the 9168 bp coding region of the ATM (ataxia telangiectasia mutated) gene. Over 68 different dye-labeled single-stranded nucleic acid targets representing all ATM coding exons were applied to these microarrays. We assess hybridization specificity by comparing the relative hybridization signals from probes perfectly matched to ATM sequences to those containing mismatches. Probes complementary to two base substitutions displayed the highest average specificity followed by those complementary to single base substitutions, single base deletions and single base insertions. In all the cases, hybridization specificity was strongly influenced by sequence context and possible intra- and intermolecular probe and/or target structure. Furthermore, single nucleotide substitution probes displayed the most consistent hybridization specificity data followed by single base deletions, two base deletions and single nucleotide insertions. Overall, these studies provide valuable empirical data that can be used to more accurately model the hybridization properties of insertion and deletion probes and improve the design and interpretation of oligonucleotide microarray-based resequencing and mutational analysis.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

Impact of gene polymorphisms on clinical outcome for stage IV melanoma patients treated with biochemotherapy: an exploratory study.

PURPOSE: Biochemotherapy can achieve high response rates in advanced melanoma, but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis that cytokine gene polymorphisms predict clinical outcome in stage IV melanoma patients treated with biochemotherapy. EXPERIMENTAL DESIGN: Ninety patients with stage IV melanoma were treated with biochemotherapy, including cisplatin, vinblastine, and dacarbazine combined with interleukin (IL)-2 and IFN-alpha either with or without tamoxifen. Cytokine gene polymorphisms for IFN-gamma (+874A-->T) and IL-10 (-1082G-->A) were assessed. X-ray repair cross-complementing gene 1 (XRCC1; Arg399Gln), xeroderma pigmentosum complementary group D (XPD; Lys751Gln), and excision repair cross-complementing gene 1 (ERCC1; codon 118) DNA repair polymorphisms were also determined. RESULTS: IFN-gamma (+874A-->T) gene polymorphism was statistically significantly associated with response (P = 0.001), progression-free survival (P = 0.0012), and overall survival (P < 0.001), whereas the IL-10 polymorphism was marginally associated with response (P = 0.03) and overall survival (P = 0.065). Multivariate analysis revealed that IFN-gamma (+874A-->T) independently predicted overall survival (P = 0.003). The ERCC1 polymorphism was weakly associated with overall survival (P = 0.045). Combining polymorphisms for IFN-gamma, IL-10, and ERCC1 stratified patients into four distinct groups with significantly different clinical outcome (P < 0.001), so that patients with more "favorable" polymorphisms had a better outcome. CONCLUSIONS: Cytokine gene polymorphisms predicted clinical outcome for advanced melanoma patients who received biochemotherapy. The combined effects of multiple genetic polymorphisms may provide more accurate prognostic information. Additional independent studies are needed to confirm these pilot findings.

Adolescent↗