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Print ArticleA newly identified gene expression profile could help predict how patients with advanced ovarian cancer will respond to chemotherapy treatment. Described in a study in the November 1, 2005 issue of The Journal of Clinical Oncology (JCO), the new findings further establish an important role for microarray gene profiling as a predictor of clinical outcome in ovarian cancer, and could eventually provide clinicians with insights into the mechanisms of drug resistance.
"In many patients with advanced ovarian cancer, post-operative treatment with first-line chemotherapy will result in an excellent clinical response," says senior author Stephen A. Cannistra, MD, director of gynecologic oncology at Beth Israel Deaconess Medical Center (BIDMC) and professor of medicine at Harvard Medical School.
"However," he adds, "due to the lingering presence of chemotherapy-resistant cancer cells, most patients will unfortunately experience a relapse. The goal of our current research is to help determine which patients will relapse and which will not, and to better understand the reasons for this."
Cannistra's group has been working to develop a genetic profile of ovarian cancer that will enable clinicians to more accurately determine a patient's prognosis. As a first step in this process, he and his colleagues last year identified a gene expression profile known as the Ovarian Cancer Prognostic Profile (OCPP), which is predictive of survival in patients with advanced ovarian cancer. (These study results appear in the December 2004 issue of the JCO.)
Their work makes use of a DNA technology known as microarray analysis, in which genes expressed by cancer cells are labeled and applied to a glass slide containing embedded sequences of thousands of known human genes. The genes that are present in the tumor cell bind to their counterpart sequences on the slide and can then be identified through computer analysis.
In this new study, the authors conducted microarray testing on samples from 60 ovarian cancer patients treated at BIDMC and Memorial Sloan-Kettering Cancer Center to determine if tumor tissue obtained at a patient's initial diagnosis expressed a gene profile predictive of findings at second-look surgery. (Second-look surgery is currently the most sensitive investigational approach for detecting residual disease in patients with advanced ovarian cancer who have achieved a complete clinical remission following chemotherapy, explains Cannistra.)
The expression of 93 genes, collectively referred to as the Chemotherapy Response Profile (CRP), was found to predict which patients would experience a complete response to chemotherapy, as defined by the absence of disease at the time of second-look surgery. The CRP also confirmed the importance of genes such as BAX in this process, which regulate the cell's response to chemotherapy agents such as paclitaxel.
The authors then went on to compare the results of the CRP and the OCPP. "We found that together these two gene profiles [CRP and OCPP] are a more powerful predictor of a patient's prognosis than either profile separately," says Cannistra. "This represents the first time that two profiles have been combined to yield such a powerful result in this disease."
One of the most difficult types of cancer to treat, advanced ovarian cancer accounts for approximately 26,000 new cases and 16,000 deaths in the U.S. each year.
"Being able to identify the expression pattern of these genes from the original tumor sample [i.e. whether genes were 'turned on' or 'turned off'] provides us with valuable information about a patient's prognosis as this type of information cannot always be obtained from standard clinical features, such as tumor grade or residual disease status," notes Cannistra. "And with the identification of each new gene expression profile, we come one step closer to eventually being able to develop treatments tailored to individual ovarian cancer patients."
Coauthors of the study include BIDMC investigators Dimitrios Spentzos, MD, Douglas Levine, MD, Towia A. Libermann, PhD, Shakirahimed Kolia and Hasan Out and Jeff Boyd, PhD, of Memorial Sloan-Kettering Cancer Center in New York.
Source : Beth Israel Deaconess Medical Center
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Functional profiling with cell culture assays that predicts for patient survival in ovarian cancer
There is Functional Profiling (whole cell profiling) that shows data indicating a near doubling in the survival of patients with platinum-resistant ovarian cancer, striking correlations between platinum activity and patient survival in previously-untreated ovarian cancer, and a comprehensive meta-analysis of scores of studies reporting response and survival correlations in thousands of patients.
With relapsed, platinum-resistant ovarian cancer, every clinical trial in history has just shown a 10-12 month median survival in this setting. However, background data (680 fresh surgical specimens) for the design of a cliinical trial to determine the efficacy of assay-directed therapy of platinum-resistant ovarian cancer, submitted to the 2003 Society of Gynecologic Oncology meeting, had a 27 month median survival and a fair number of long-term survivors. All specimens were tested with two separate Medicare-approved cell culture assays (DISC and MTT) having cell-death endpoints.
Cell culture drug resistance testing in platinum-resistant ovarian cancer
Sub-category: Translational research
Category: Ovarian
Control/Tracking Number: 2004-AB-171-SGO
Activity: Abstract Richard H. Nalick, Hospital of the Good Samaritan, Los Angeles, CA; Larry M. Weisenthal, Weisenthal Cancer Group, Huntington Beach, CA
Objectives: Obtained background data required for the design of a clinical trial to determine the efficacy of assay-directed therapy of platinum-resistant ovarian cancer.
Methods: 680 fresh surgical specimens of ovarian cancer were submitted from outside hospitals for the purpose of obtaining cell culture assay data to assist in the choice of chemotherapy on a non-investigational basis. Virtually all surgical specimens were tested with two separate Medicare-approved cell culture assays (DISC and MTT) having cell-death endpoints.
Results: Validation of cell culture assays for identifying platinum resistance was as follows.
1. Surgical specimens from platinum-treated patients had significantly greater in vitro resistance to platinum than surgical specimens from untreated patients.
2. Untreated patients without in vitro resistance to platinum had significantly better long-term, overall survival than patients with in vitro resistance to platinum (2775 vs 713 days, P2=0.0066).
3. Surgical specimens obtained within 6 months of platinum-based therapy had significantly greater in vitro resistance to platinum than surgical specimens obtained more than 6 months after the last platinum-based therapy.
4. In patients more than 6 months after the last platinum-based therapy, in vitro resistance to platinum predicted for significantly inferior long-term, overall survival (950 days vs median not reached, P2<0.05).
Comparing early relapse surgical specimens with untreated surgical specimens, the following regimens showed significantly inferior activity in early relapse surgical specimens: cisplatin, carboplatin, oxaliplatin, melphalan, thiotepa, mitomycin, paclitaxel, and the topotecan + cicplatin combination. The following did not show significantly inferior activity in ER surgical specimens: gemcitabine, etoposide, vinorelbine, fluorouracil, epirubicin, pegylated doxorubicin, topotecan, irinotecan, docetaxel, and all 3 gemcitabine + platinum combinations. Although the gemcitabine + platinum combination was the only active regimen in 25% of the early relapse surgical specimens, in 30% there was at least one active single agent, and in another 20%, other drug combinations were superior to gemcitabine + platinum, some of these being irinotecan + mitomycin, paclitaxel + cyclophosphamide, cyclophosphamide + etoposide, platinum + topotecan, and gemcitabine + melphalan. With a minimum follow-up of 3 years post-assay, early relapse (primary refractory and first relapse) patients had a median long-term, overall survival of 849 days, while all early relapse patients (including multiple relapse) had a median survival of 612 days. All late relapse patients had a median long-term, overall survival of 1244 days.
Conclusions: These results support a 3-armed, prospective randomized trial in early relapse patients to compare physician's choice chemotherapy, assay-directed therapy, and the 3 gemcitabine + platinum combination.
There have been 5 different studies of the relationship between the results of Cell Culture Assay Testing and patient survival in ovarian cancer, and all 5 studies show significant correlations between these assays and patient survival.
http://weisenthal.org/ov_surv.htm
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