Biomedical subjects

Kathleen M Darcy

Publications and source records attributed to Kathleen M Darcy.

11 recordsLinked to original sources

PubMed2025

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Journal Article↗

PubMed2006

Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: a gynecologic oncology group study.

PURPOSE: To evaluate the anti-tumor activity and adverse events of capecitabine in advanced, persistent or recurrent squamous cell carcinoma of the cervix, and to explore biomarkers with the potential to predict capecitabine response and toxicity. EXPERIMENTAL DESIGN: Eligible, consenting patients were treated with a starting dose of 2500 mg/m(2)/day or 1800 mg/m(2)/day (divided into two doses given every 12 h) for 14 days of each 21-day cycle. Prior chemotherapy was allowed only in the context of radiation "sensitization". Genotyping in the 5' and 3' ends of thymidylate synthase (TS) was performed in DNA from pretreatment blood. Relative gene expression of TS, dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) was quantified in RNA extracted from paraffin-embedded tumor. RESULTS: All patients had prior radiotherapy and 22 received a radiation sensitizer. A partial response was observed in 4 of 26 (15%) evaluable patients. An additional 35% of patients achieved stable disease while 42% experienced increasing disease. The most common serious non-hematological toxicities were gastrointestinal and dermatologic. Exploratory analyses suggested that: a germline polymorphism in the 3' or the 5' end of TS was not associated with TS gene expression, relative tumor expression of TS, DPD and TP were not correlated, and relative tumor expression of TP may predict severe anemia. CONCLUSIONS: Based on the modest response rate, this trial was closed without a second stage of accrual; single agent capecitabine was not selected for further study in advanced persistent or recurrent squamous cell carcinoma of the cervix previously treated with radiation or chemoradiation.

Adult↗

PubMed2006

Relevant molecular markers and targets.

Ovarian cancer is a heterogeneous disease with extensive cytogenetic and molecular heterogeneity including aneuploidy, chromosomal alterations, mutations and overexpression as well as a natural propensity to disseminate and spread, making it difficult to diagnose at an early stage. Insights into the molecular mechanisms operative in cancer development, progression and metastasis have uncovered a wide array of targets for therapeutic intervention. In the absence of a common driving oncogene in ovarian cancer, single targeted therapy for this disease is unlikely to yield significant clinical benefit. Tailored approaches that combine molecular targeting agents with cytotoxic regimens hold great promise when used in primary treatment, during consolidation and maintenance therapy, and in the treatment of persistent or recurrent disease. The most promising treatment strategies are those that target the drivers of tumorigenesis and enhance the activity of cytotoxic agents. Receptor tyrosine kinases, non-receptor tyrosine kinases, serine/threonine kinases, transferases, proteases and deacetylases are among the relevant molecular markers and targets for ovarian cancer that are discussed. Collaboration, coordination, creativity and aggressive outreach to patients and their advocates are essential for success in running the concurrent trials with multiple clinical end points and embedded translational research that are needed to evaluate the array of promising targeted therapeutics and combinations. Validated biomarkers, surrogate specimens and end points, and additional clinically relevant in vitro and in vivo models for ovarian cancer are needed to facilitate the drug development and evaluation process, and ultimately to make meaningful improvements in the diagnosis, prevention and management of ovarian cancer.

Biomarkers, Tumor↗

PubMed2006

Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: a Gynecologic Oncology Group study.

OBJECTIVE: To determine if smoking, a known risk factor for a number of cancers including cervical cancer, is associated with poor prognosis in patients with locally advanced cervical carcinoma treated with chemoradiation. METHODS: Patients with primary, previously untreated, histologically confirmed stage II-B, III-B or IV-A cervical carcinoma participated in a Gynecologic Oncology Group (GOG) phase III study (GOG 165) and were randomly allocated to receive radiation plus either cisplatin or 5-fluorouracil. Smoking behavior was ascertained using an administered questionnaire and by quantifying urine cotinine concentration. Disease progression was defined as a >or=50% increase in the cross product of the existing tumor compared with previous assessments. Patients were followed until death. RESULTS: Of 328 enrolled patients, 12 were ineligible, one was inevaluable for reported smoking status and 40 others were inevaluable for cotinine-derived smoking status. Among evaluable patients, 133 (42%) were reported smokers and 111 (40%) were cotinine-derived smokers. The kappa for agreement between the groups was 0.872 (P<0.01). Compared with non-smokers, median survival was 15 months shorter for reported smokers and 20 months shorter for cotinine-derived smokers (P<0.01). After adjusting for covariates, a significant increase in the risk of death (but not disease progression) was observed for reported smokers (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.01-2.27; P=0.04) and cotinine-derived smokers (HR: 1.57; 95% CI: 1.03-2.38; P=0.04). CONCLUSIONS: Smoking predicts worse overall survival in women with locally advanced cervical carcinoma treated with chemoradiation.

Adenocarcinoma↗

PubMed2006

Maspin expression in epithelial ovarian cancer and associations with poor prognosis: a Gynecologic Oncology Group study.

OBJECTIVE: This study examined MASPIN expression in human ovarian cancer, and explored the association between MASPIN and prognosis in patients with advanced stage disease treated with first-line cisplatin, carboplatin and/or paclitaxel. METHODS: Frozen primary tumors were obtained from 68 women with previously untreated, advanced stage epithelial ovarian cancer who participated in a specimen banking protocol and a phase III treatment trial conducted by the Gynecologic Oncology Group. Immunoblot analysis was performed in lysates prepared from these tumor specimens to quantify the relative expression of MASPIN/beta-actin. RESULTS: MASPIN was expressed at detected levels in 49 (72%) cases with relative expression ranging from 0.02 to 7.7 (median = 0.2), and was not detected in 19 (28%) of the primary tumors tested. Non-detectable levels of this class II tumor suppressor gene product and inhibitor of angiogenesis were associated with suboptimally-debulked disease (P = 0.034) but not with patient age, FIGO stage, tumor grade, or histologic subtype. After adjusting for prognostic variables for disease progression or death, non-detectable MASPIN expression predicted an increased risk of disease progression (hazard ratio [HR] = 1.89; 95% confidence interval [CI]: 1.04-3.45; P = 0.038) and death (HR = 1.99; 95% CI: 1.07-3.69; P = 0.030). CONCLUSIONS: In advanced stage epithelial ovarian cancer, non-detectable MASPIN appears to be associated with suboptimally-debulked disease and be an independent predictor of an increased risk of progression and death. Further studies are needed to validate these exploratory findings, determine the molecular mechanism controlling MASPIN expression as well as down-regulation and loss in ovarian cancer, and determine if MASPIN can prevent progression of this disease.

Actins↗

PubMed2006

Population analysis of a 24-h paclitaxel infusion in advanced endometrial cancer: a gynaecological oncology group study.

AIMS: To examine determinants of paclitaxel disposition and the association between paclitaxel exposure and toxicity or survival in patients with advanced stage or recurrent endometrial cancer treated with doxorubicin plus paclitaxel. METHODS: A limited sampling scheme was used to examine the population pharmacokinetics of paclitaxel in 160 patients from one arm of a randomized Phase III trial of doxorubicin plus paclitaxel or cisplatin. Four plasma samples per patient were collected at approximately 0, 3, 22 and 27 h after the first 24-h infusion of paclitaxel and submitted to the Gynecological Oncology Group (GOG) Pharmacology Core Laboratory. Total paclitaxel concentrations were quantified by LC/MS and paclitaxel disposition was examined using NONMEM. Paclitaxel exposure was evaluated for associations with toxicity or survival. RESULTS: Patient weight, age and serum glutamic-oxaloacetic transaminase level were determinants of paclitaxel clearance (clearance increased 0.437 l h-1 kg-1; decreased 0.223 l h-1 year-1 and 0.105 l h-1 IU-1). Bayesian shrinkage was minimal for this parameter. In different measures of paclitaxel exposure, AUC was most predictive of toxicity, with higher AUC associated with granulocytopenia [probability of 1% at AUC=1 to 22% at AUC=4 microg l-1 h-1 for performance status (PS)=0]. PS was more strongly associated with survival than disease stage and higher paclitaxel AUC was associated with worse survival irrespective of PS and stage. CONCLUSIONS: Paclitaxel AUC is an independent predictor of granulocytopenia and survival in patients with advanced stage or recurrent endometrial cancer. Future studies are needed to validate the latter finding. This study confirms the appropriateness of evaluating pharmacokinetics and pharmacodynamics in multicentre oncology trials.

Adult↗

PubMed2005

Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study.

PURPOSE: This phase II trial assessed the activity and tolerability of a daily oral dose of 500 mg gefitinib (ZD1839, Iressa) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma, and explored the clinical value of determining the status of the epidermal growth factor receptor (EGFR). EXPERIMENTAL DESIGN: Primary measure of efficacy was progression-free survival at 6 months. Mutations in exons 18 to 21 of EGFR and/or immunohistochemical expression of EGFR were evaluated in tumor specimens from patients enrolled in this trial as well as from patients not treated with gefitinib. RESULTS: Twenty-seven of 30 (90%) patients were eligible and evaluable for analysis of gefitinib efficacy and toxicity. Of these, four survived progression-free >6 months with one objective response (4%). The most commonly observed grade 3 toxicities were dermatologic (15%, 4 of 27) and diarrhea (30%, 8 of 27). Specimens from 26 of 26 or 25 of 26 patients were evaluable for immunohistochemical or mutation analysis, respectively. The response rate for patients with EGFR-positive tumors was 9% (1 of 11). EGFR expression was associated with longer progression-free survival (P = 0.008) and possibly longer survival (P = 0.082). The patient with the only objective response had a mutation in the catalytic domain of the tumor's EGFR (P = 0.04). Among 32 invasive tumors from patients not treated with gefitinib, one exhibited a catalytic domain mutation. CONCLUSIONS: Gefitinib was well tolerated but had minimal activity in unscreened patients with recurrent ovarian or primary peritoneal carcinoma. Prescreening patients for activating mutations in EGFR may improve response rate to gefitinib. This report is the first to document activating mutations in catalytic domain of EGFR in 3.5% (2 of 57) of ovarian cancers.

Adult↗

PubMed2005

Phase II clinical trial of capecitabine in ovarian carcinoma recurrent 6-12 months after completion of primary chemotherapy, with exploratory TS, DPD, and TP correlates: a Gynecologic Oncology Group study.

PURPOSE: A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of capecitabine in women with measurable platinum-sensitive ovarian cancer or platinum-sensitive primary peritoneal cancer and to explore the ability of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) to predict response and toxicities. EXPERIMENTAL DESIGN: Patients were treated with a daily starting dose of 2500 mg/m2/day (divided in two doses given every 12 h) for 14 days of each 21-day cycle. Genotyping in the 5' and 3' ends of TS was performed in DNA from 23/23 pre-treatment blood specimens. Relative gene expression of TS, DPD, and TP was quantified in 18/21 paraffin-embedded tumor specimens. RESULTS: Of the 27 patients enrolled on study, 2 were never treated leaving 25 patients evaluable. Two patients (8.0%) achieved a partial response, 13 (52%) exhibited stable disease, 5 (20%) displayed increasing disease, and response could not be assessed in 5 (20%). The median time to progression and survival was 3.9 and 21.2 months, respectively. The most common serious toxicities were nausea/vomiting, gastrointestinal, and dermatological. There was one treatment-related death. TS expression was associated with severe nausea/vomiting (P = 0.039), but not with other severe toxicities. TS genotype or expression of DPD or TP was not associated with any of the severe toxicities. CONCLUSIONS: Based on the low response rate, this trial was closed after the first stage of accrual, the drug was not selected for further study in this patient population, and biomarker associations with response could not be assessed.

Adult↗

PubMed2004

Association between serum levels of soluble tumor necrosis factor receptors/CA 125 and disease progression in patients with epithelial ovarian malignancy: a gynecologic oncology group study.

BACKGROUND: A prospective study was undertaken within the Gynecologic Oncology Group to determine whether serum levels of soluble tumor necrosis factor receptors I (sTNFR-I) and II (sTNFR-II), alone or in combination with CA 125, were associated with clinicopathologic characteristics or outcome in patients with epithelial ovarian malignancies. METHODS: Quantitative immunoassays were performed on valid pretreatment serum specimens obtained from patients with epithelial ovarian malignancies to assess levels of sTNFR-I, sTNFR-II, and CA 125. The authors then analyzed the results of these immunoassays for potential correlations with clinicopathologic characteristics and outcome. RESULTS: The median age of the 139 women evaluated was 59 years. Seventy-eight percent had Stage III or IV disease, and 58% had serous carcinomas. sTNFR-II was associated with age (P = 0.013), and CA 125 was associated with histologic subtype (P = 0.0009). In addition, sTNFR-I (P = 0.037) and CA 125 (P < 0.0001) were associated with extent of disease. After adjusting for patient age, histologic subtype, and extent of disease, all three biomarkers were predictive of progression-free survival, but not overall survival, when the combination was included in the model. The authors observed a 51% reduction (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.24-0.99), a 2.9-fold increase (HR, 2.87; 95% CI, 1.15-7.20), and a 22% increase (HR, 1.22; 95% CI, 0.99-1.51) in the risk of progression for each unit increase in the log-transformed levels of sTNFR-I, sTNFR-II, and CA 125, respectively. CONCLUSIONS: The observations made in the current study-that among patients with low or high CA 125 levels, those with high sTNFR-I levels and low sTNFR-II levels had the lowest risk, that patients with low-low or high-high sTNFR-I and sTNFR-II levels, respectively, had an intermediate risk, and that patients with low sTNFR-I levels and high sTNFR-II levels had the highest risk of progression-suggested the potential value of simultaneous assessment of all three biomarkers in patients with epithelial ovarian malignancies.

Aged↗

PubMed2003

Cyclin E expression is a significant predictor of survival in advanced, suboptimally debulked ovarian epithelial cancers: a Gynecologic Oncology Group study.

Cyclin E is a key regulator of the G(1)-S transition. Abnormalities in cyclin E expression have been related to survival in a variety of cancers. This study evaluated the prognostic relevance of cyclin E in human ovarian cancer. Immunohistochemical expression of cyclin E was evaluated in 139 advanced, suboptimally debulked epithelial ovarian cancer specimens from patients treated on Gynecologic Oncology Group protocol 111. High cyclin E protein expression (> or =40% cyclin E positive tumor cells) was seen in 62 (45%) of the advanced, suboptimally debulked ovarian cancer patients. Expression of cyclin E was not associated with age, race, stage, grade, cell type, or amount of residual disease. High verses low cyclin E expression was associated with a shorter median survival (29 +/- 2 versus 35 +/- 3 months) and worse overall survival (P < 0.05). Univariate and multivariate regression analyses revealed that high relative to low cyclin E was associated with a 40-50% increase in the risk of death (hazard rate, P < or = 0.05). Fluorescence in situ hybridization was used in a subset of 20 cases to examine cyclin E gene amplification. Eight of 10 cases with high cyclin E expression exhibited amplification of the cyclin E gene, whereas only 1 of 10 cases with low expression displayed gene amplification (P < 0.006). High cyclin E expression was an independent poor prognostic factor for patients with advanced ovarian cancer, and it was associated with amplification of the cyclin E gene.

Aged↗

PubMed2003

Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group.

PURPOSE: To evaluate the feasibility, toxicity, and efficacy of single-agent monoclonal antibody therapy targeting the human epidermal growth factor receptor 2 (HER2)/neu receptor in ovarian and primary peritoneal carcinoma. PATIENTS AND METHODS: Eligible patients had measurable persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+ or 3+ HER2 overexpression documented by immunohistochemistry. Intravenous trastuzumab was administered initially at a dose of 4 mg/kg, then weekly at 2 mg/kg. Patients without progressive disease or excessive toxicity could continue treatment indefinitely. Those with stable or responding disease at 8 weeks were offered treatment at a higher weekly dose (4 mg/kg) at time of progression. Patient sera were analyzed for the presence of the soluble extracellular domain of HER2, host antibodies against trastuzumab, and trastuzumab pharmacokinetics. RESULTS: A total of 837 tumor samples were screened for HER2 expression, and 95 patients (11.4%) exhibited the requisite 2+/3+ expression level. Forty-five patients, all of whom received prior chemotherapy, were entered, and 41 were deemed eligible and assessable. There were only mild expected toxicities and no treatment-related deaths. Although an elevated level of the soluble extracellular domain of HER2 was detected in eight of 24 patients, serum HER2 was not associated with clinical outcome. There was no evidence of host antitrastuzumab antibody formation. Serum concentrations of trastuzumab gradually increased with continued therapy. An overall response rate of 7.3% included one complete and two partial responses. Median treatment duration was 8 weeks (range, 2 to 104 weeks), and median progression-free interval was 2.0 months. CONCLUSION: The clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 overexpression and low rate of objective response among patients with HER2 overexpression.

Adenocarcinoma, Clear Cell↗