Estrogen receptor promoter methylation predicts survival in low-grade ovarian carcinoma patients

Purpose

Ovarian carcinoma is the third most common gynecological cancer and only short recurrence-free survival and overall survival times are archived. The role of the estrogen receptor expression is well studied in breast cancer and breast cancer cell lines. Patients with positive estrogen receptor expression have a lower risk for recurrence and a better overall survival. Previous studies have shown that ESR1 methylation influences ovarian cancer development and might thus play a role regarding prognosis of ovarian carcinoma.

Methods

A total of 75 patients were identified that were treated for ovarian carcinoma by debulking surgery and adjuvant standard chemotherapy. Isolation and bisulfite treatment of genomic DNA from serial sections of surgically resected ovarian carcinoma tissue was performed using commercially available kits. For the detection of methylated ESR1 promoter sequences, real-time methylation-specific PCR was used.

Results

Promoter methylation did not show a correlation between clinical–pathological data for all patients. However, within the subgroup of low-grade ovarian carcinoma patients and patients with an ovarian tumor of low malignant potential methylation of the ESR1 promoter inversely correlated with survival (p = 0.031).

Conclusions

Although small numbers of ovarian carcinoma patients were analyzed, methylation status might be useful as a prognostic marker within the subgroup of low-grade ovarian carcinoma patients. Further studies should investigate a larger cohort and also address the use of demethylation agents with respect to improve patient’s prognosis in this subgroup of ovarian carcinoma patients.     

Effect of chemotherapy on survival after whole brain radiation therapy for brain metastases: a single-center retrospective analysis

Background and purpose

Whether chemotherapy for systemic disease affects survival of patients with brain metastases or not has not been elucidated before. We performed comprehensive analysis of patients with newly-diagnosed brain metastases primarily treated with whole brain radiation therapy (WBRT) alone.

Materials and methods

Data from 134 patients with newly-diagnosed brain metastases primarily treated with WBRT from 2007 to 2008 was retrospectively reviewed. Univariate and multivariate analyses were performed to identify significant prognostic factors.

Results

Median survival time (MST) of this cohort from the start of WBRT was 5.7?months. MST of patients with RPA Class 1, 2 and 3 were 10.3, 7.8 and 2.2?months, respectively. Multivariate analysis revealed that karnofsky performance status (≥70, p?p?p?=?0.015), time to develop brain metastasis (<3?months, p?=?0.042) and use of chemotherapy after WBRT (multiple regimens, p?Conclusions Systemic chemotherapy for chemo-responsive cancer prolongs survival despite the presence of treated brain metastases. Irradiated brain metastases will lose their prognostic significance in a large number of patients. Systemic chemotherapy will be a treatment of choice for patients who have systemic disease after WBRT for brain metastases. These results should be validated in the future prospective clinical trials.     

Thymidine kinase: a tumor marker with prognostic value for non-Hodgkin's lymphoma and a broad range of potential clinical applications

Summary Thymidine kinase (TK) is a cellular enzyme which is involved in a salvage pathway of DNA synthesis. It is activated in the G1/S phase of the cell cycle, and its activity has been shown to correlate with the proliferative activity of tumor cells. Additionally, certain viruses are able to induce cellular TK production and activity. Clinical studies have reported elevated serum TK levels in a variety of neoplasias. The majority of these studies concerned hematologic malignancies. TK seems to be a useful marker in non-Hodgkin's lymphoma, where it correlates with clinical staging and provides significant prognostic information on (progression-free) survival. Preliminary results in acute myeloid leukemia indicate that pretreatment serum TK values may predict the response to the first induction chemotherapy. Moreover, serum TK appears to have some clinical value in such solid tumors as prostate cancer, breast cancer, and small-cell lung cancer, whereas it is not a reliable marker of non-small-cell lung cancer and brain tumors.Supported in part by grants Ha 1680/1-1 and Ha 1680/1-2 of theDeutsche Forschungsgemeinschaft (to M.H.)     

Treatment of clinical stage I testicular cancer and a possible role for new biological prognostic parameters

Three different treatment strategies for patients with stage I non-seminomatous testicular cancer are available that will all result in long-term survival in more than 98% of the patients: a wait and see strategy with follow-up and chemotherapy in cases of tumour progression, retroperitoneal lymphadenectomy, with or without application of systemic chemotherapy, in cases of retroperitoneal metastases (pathological stage II disease) or primary adjuvant chemotherapy following inguinal orchiectomy. Each treatment strategy is associated with specific side-effects. In several studies histological characteristics of the primary tumour, particularly the presence of vascular invasion and of embryonal carcinoma cells, have been demonstrated to be significant prognostic factors for the risk of occult retroperitoneal metastases in patients with stage I disease. In addition, new biological prognostic factors determined by flow cytometry, cytogenetic analysis or molecular-biological DNA or RNA analysis have been investigated, among which alterations of thep53 tumour-suppressor gene may represent a promising new prognostic factor. Although alterations ofp53 gene expression seem to be associated with advanced tumour stage and may predict retroperitoneal metastatic disease, the independent role of these molecular genetic alterations needs to be prospectively studied. Currently a risk-adapted treatment strategy based on the histological criteria of vascular invasion and the presence of embryonal carcinoma can be used to stratify patients into a high- and low-risk group with respect to tumour progression. While primary-nervesparing retroperitoneal lymphadenectomy or adjuvant chemotherapy with two cycles of platinum, etoposide and bleomycin may be appropriate for patients with a high risk (above 40%) for tumour progression, a wait-and-see strategy can be used for low-risk (less than 15% risk of progression) patients. Molecular investigations of prognostic factors may be able to improve further the stratification of patients into these different risk categories.Abbreviations RLA retroperitoneal lymphadenectomy - SCF stem-cell factor     

Geriatric oncology: perspectives from decision analysis. A review

The management of advanced cancer in the older person is variable. In some patients with common malignancies chemotherapy may palliate symptoms and prolong survival, while in other patients chemotherapy is a cause of overwhelming toxicity and supportive care is the preferred form of treatment. We explored the principles of individualized management for the older person with cancer and we used decision analysis as a guide. From a decisional standpoint, geriatric malignancies may be subdivided into two categories: diseases whose management is not affected by age and diseases whose management may be age-conditioned. In the latter group one can distinguish three clinical situations: diseases with short survival when untreated, which are responsive only to highly toxic chemotherapy; diseases with short survival when untreated, which may be responsive to low-toxicity chemotherapy; and diseases with prolonged survival when untreated, whose clinical course may be affected by chemotherapy. From the analysis of these clinical situations, a critical paucity of information has emerged in five areas: prognostic evaluation of the older patients, interaction of comorbid conditions and cancer chemotherapy, availability of low-toxicity alternative treatment regimens, life expectancy and estimate of outcome utilities. Further research in these areas, according to the lines we propose, may fill critical gaps of knowledge and allow optimal management of geriatric cancer.     

Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients

The validation of prognostic biomarkers in large independent patient cohorts is a major bottleneck in ovarian cancer research. We implemented an online tool to assess the prognostic value of the expression levels of all microarray-quantified genes in ovarian cancer patients. First, a database was set up using gene expression data and survival information of 1287 ovarian cancer patients downloaded from Gene Expression Omnibus and The Cancer Genome Atlas (Affymetrix HG-U133A, HG-U133A 2.0, and HG-U133 Plus 2.0 microarrays). After quality control and normalization, only probes present on all three Affymetrix platforms were retained (n=22,277). To analyze the prognostic value of the selected gene, we divided the patients into two groups according to various quantile expressions of the gene. These groups were then compared using progression-free survival (n=1090) or overall survival (n=1287). A Kaplan-Meier survival plot was generated and significance was computed. The tool can be accessed online at www.kmplot.com/ovar. We used this integrative data analysis tool to validate the prognostic power of 37 biomarkers identified in the literature. Of these, CA125 (MUC16; P=3.7×10(-5), hazard ratio (HR)=1.4), CDKN1B (P=5.4×10(-5), HR=1.4), KLK6 (P=0.002, HR=0.79), IFNG (P=0.004, HR=0.81), P16 (P=0.02, HR=0.66), and BIRC5 (P=0.00017, HR=0.75) were associated with survival. The combination of several probe sets can further increase prediction efficiency. In summary, we developed a global online biomarker validation platform that mines all available microarray data to assess the prognostic power of 22,277 genes in 1287 ovarian cancer patients. We specifically used this tool to evaluate the effect of 37 previously published biomarkers on ovarian cancer prognosis.     

Attenuated expression of SECIS binding protein 2 causes loss of telomeric reserve without affecting telomerase

The family of selenoproteins have a broad range of functions, including protection against oxidative damage. Previous studies have shown that elevated levels of oxidative damage can induce accelerated loss of telomeric DNA during proliferation of mammalian cells. The incorporation of selenocysteine (Sec) into proteins in mammalian cells requires the Sec insertion sequence (SECIS) binding protein 2 (SBP2). Thus in the present study we have assessed the effect of knocking down the expression of SBP2 on telomere length. Following knock-down of SBP2 expression in two different human cell lines, the MSTO mesothelioma cell line (5 Kb average telomere length) and SY5Y neuroblastoma cell line (4.2 Kb average telomere length), we observed a significant reduction (−0.6 to −1.1 Kb; P  0.01) in telomere length as compared to control cells. This reduction in telomere length was independent of affects on telomerase, since both telomerase activity levels and Tert mRNA expression levels were not altered by knock-down of SBP2 expression. Furthermore, telomeres were particularly sensitive to S1 nuclease digestion following SBP2 knock-down, indicating an increased frequency of oxidative damage-induced lesions in the telomeric DNA in these cells. Together, these observations imply that selenoproteins may help protect telomeric reserve in mammalian cells.     

Association between pretreatment CA-125 levels and surgically documented complete responses in patients with ovarian cancer treated with second-line intraperitoneal therapy

Summary Approximately 20%–40% of patients with small-volume residual ovarian cancer, following systemically administered platinum-based chemotherapy, will respond to a second-line intraperitoneal treatment regimen. In an effort to improve the selection criteria for patients being considered for this regional therapeutic approach, we retrospectively evaluated the influence of pretreatment CA-125 levels on the ability of a group of 70 patients with small-volume residual ovarian cancer (no tumor mass>1 cm in diameter) to achieve a surgically defined complete response (S-CR) following treatment on one of three phase-2 intraperitoneal chemotherapy trials conducted at the Memorial Sloan-Kettering Cancer Center. Overall, 18/46 (39%) patients with normal pretreatment CA-125 levels (units/ml) achieved a S-CR, compared to only 4/24 patients (17%) with an elevated pretreatment value (²= 3.7, P>0.5). Despite the lower S-CR rate in patients with elevated CA-125 levels, the duration of response and survival were similar in the two patient populations achieving a S-CR. Thus, we conclude that an elevated pretreatment CA-125 level in a patient with small-volume residual ovarian cancer should not be used by itself to disqualify an individual from consideration for a second-line intraperitoneal treatment regimen, although the finding suggests a reduced likelihood of achieving a S-CR with this therapeutic approach.Abbreviations S-CR surgically defined complete response Supported in part by the Avon Program in Ovarian Cancer, Memorial Sloan-Kettering Cancer Center and NCI grant CA-05826     

Role of radical surgery in patients with stage IV gallbladder cancer

Objectives

The role of surgery in stage IV gallbladder (GB) cancer is not well established. This study analyses prognostic factors in patients with stage IV GB cancer following surgical resection with the aim of identifying a subgroup of patients who might benefit from surgical resection.

Methods

Clinicopathological details were analysed for 94 patients who were surgically treated for stage IV GB cancer at Seoul National University Hospital.

Results

Median survival was 8 months in patients with either stage IVa or IVb disease. Sixteen patients (17.0%) underwent resection with curative intent, which increased overall survival over that in patients undergoing palliative surgery (P < 0.001). No survival benefit was seen following surgery with curative intent in patients with stage IVa disease (P = 0.764). Surgery with curative intent resulted in a survival benefit in patients with stage IVb disease, patients with an isolated liver metastasis near the GB bed (median survival: 31 months vs. 9 months; P < 0.001) and patients with limited numbers of peritoneal implantations (median survival: 20 months vs. 6 months; P = 0.002). Preoperative serum carcinoembryonic antigen (CEA) (P = 0.018), surgery with curative intent (P = 0.045) and adjuvant chemotherapy (P = 0.002) were independent prognostic factors in patients with stage IV GB cancer.

Conclusions

Surgery in combination with systemic chemotherapy may be beneficial in carefully selected patients with stage IVb GB cancer.     

Salvage therapy with topotecan in heavily pretreated ovarian cancer patients

Background

We showed feasibility and efficacy of topotecan in third or a higher line of chemotherapy in heavily pretreated ovarian cancer (HPOC) patients.

Methods

Between January 2004 and June 2007, 25 cases of HPOC were treated with topotecan as 30-min infusion at the dose of 1.5 mg/m² through 5 consecutive days every 21 days. We assessed toxicity profile using NCI CTC and the response was measured according to RECIST and CA-125 criteria described by Rustin.

Results

Heavily pretreated ovarian cancer received at least two cycles of topotecan (median 6, range 2–6) with prior chemotherapy lines (median 3, range 3–7). In 20 HPOC who met RECIST criteria results were as follows: PR, 6/20 (30%); NC, 7/20 (35%); PD, 7/20 (35%). Biochemical response was noted in 20 patients having ?15% (3/20) of 75% and 20% (4/20) of 50% decline of CA-125. Time to progression was median 6 months (95% CI: 4.06–6.18) and overall survival was median 9 months (95% CI: 8.69–16.27). In multivariate analysis, primary optimal debulking and response to primary chemotherapy (HR = 0.24, 95% CI: 0.08–0.69, P = 0.0084; HR = 0.38, 95% CI: 0.14–0.98, P = 0.0448, respectively) were independent prognostic factors when assessed in relation to salvage therapy with topotecan. We did not observe difference in side effects after topotecan treatment among patients in relation to the higher number of previously used chemotherapy line (3 vs. >3).

Conclusions

We state that topotecan is able to offer a control of ovarian cancer, despite previous treatment, but reliable management is needed to alleviate hematologic toxicity.

     

Overexpression of protein S100A4 is independently associated with overall survival in stage C colonic cancer but only in cytoplasm at the advancing tumour front

Purpose

S100A4, a multifunctional protein, has been linked to the invasive growth and metastases of several human cancers. This study investigated the association between S100A4 and overall survival and other clinicopathological features in patients with stage C colonic cancer.

Methods

Clinical and pathological data were obtained from a prospective hospital registry of 409 patients who had a resection for stage C colonic cancer. Tissue microarrays for immunohistochemistry were constructed from archived tissue. S100A4 staining intensity and percentage of stained cells were assessed in nuclei and cytoplasm for both the central part of the tumour and at the advancing front. Overall survival was analysed by the Kaplan–Meier method and Cox regression.

Results

Only a high percentage of cells with S100A4 cytoplasmic staining in frontal tissue was associated with poor survival (hazard ratio, 1.6; 95?% CI 1.1–2.2; p?=?0.008) after adjustment for other prognostic variables. There was no association between frontal cytoplasmic S100A4 expression and any of 13 other clinicopathological variables.

Conclusions

High expression of S100A4 in cytoplasm at the advancing front of stage C colonic tumours indicates a poor prognosis. Whether S100A4 can predict response to adjuvant chemotherapy remains to be investigated in a randomised clinical trial.     

Clinical significance of changes in Torque teno virus DNA titer after chemotherapy in patients with primary lung cancer

Background

Several studies have reported that viral infections are related to lung cancer. We previously reported the involvement of Torque teno virus (TTV) in patients with lung cancer and idiopathic pulmonary fibrosis. However, the role of TTV in lung cancer growth, and its influence on changes in TTV DNA titers due to idiopathic pulmonary fibrosis (IPF) in lung cancer patients are poorly understood.

An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer

Individualization of cancer management requires prognostic markers and therapy-predictive markers. Prognostic markers assess risk of disease progression independent of therapy, whereas therapy-predictive markers identify patients whose disease is sensitive or resistant to treatment. We show that an experimentally derived IFN-related DNA damage resistance signature (IRDS) is associated with resistance to chemotherapy and/or radiation across different cancer cell lines. The IRDS genes STAT1, ISG15, and IFIT1 all mediate experimental resistance. Clinical analyses reveal that IRDS(+) and IRDS(−) states exist among common human cancers. In breast cancer, a seven–gene-pair classifier predicts for efficacy of adjuvant chemotherapy and for local-regional control after radiation. By providing information on treatment sensitivity or resistance, the IRDS improves outcome prediction when combined with standard markers, risk groups, or other genomic classifiers.After surgical resection of breast cancer, reducing the risk of death from metastasis with adjuvant chemotherapy (ADCT) and radiation therapy (RT) is proven to result in an absolute survival benefit of ≈5% to 10% (1, 2). For ADCT, this benefit is modest primarily for two reasons. First, only 20% to 30% of treated patients actually have occult metastases and stand to benefit. Second, among the 20% to 30% of patients with occult disease, only 30% have disease that is sensitive to treatment (Fig. 1A). Therefore, the failure to identify patients who do not have occult metastases and/or have disease that is resistant to treatment results in the majority of patients receiving adjuvant therapy without benefit. Furthermore, attempts to intensify therapy to overcome treatment resistance exacerbates the problem of over-treatment because treated patients may either not need therapy or may have shown a response to less intense regimens (Fig. 1A). Thus, to optimally tailor adjuvant therapy for a heterogeneous group of patients, we need to identify a priori which patients are at risk for occult metastasis before adjuvant therapy, and which at-risk patients have disease that is sensitive to the treatment. The former is measured by prognostic markers and the latter by predictive markers, hereafter called therapy-predictive markers.Open in a separate windowFig. 1.Therapy-predictive markers and the association of the IRDS with resistance to DNA damage. (A) The role of prognostic and therapy-predictive markers in the management of early-stage breast cancer after surgical resection is illustrated. Shown are the approximate percentages of patients expected to fall into each category. (B) Thirty-four cell lines were used in a gene set enrichment analysis (GSEA) to measure the correlation between the 49-gene IRDS and the SF2. The rank-ordered list of Pearson correlations for all 21,225 genes is shown on the bottom half of the graph with zero correlation marked (red line). The position of the IRDS genes in this list is marked in the top half of the graph (black vertical line) along with the corresponding enrichment score (green line) to reflect the degree to which the IRDS genes are over-represented. The false discovery rate (FDR) is shown. The 36 of 49 IRDS genes that are among the top 25% of all genes and considered enriched from the GSEA are indicated (blue bracket) and (C) displayed as rows in the heat map. Gene rows are ordered by correlation to the SF2 with STAT1 having the highest correlation. Cell lines in each column are ordered according to hierarchical clustering using Euclidean distance as a metric. The SF2 for each cell line is shown in the plot below the heat map. Gene expression shown in orange represents high expression and blue low expression. Similar results were obtained by restricting GSEA to the 40 of 49 up-regulated IRDS genes, collapsing probe sets to unique genes, or using the alternative gene set analysis method (P = 0.01, see SI Text).The majority of standard clinicopathologic factors, risk groups, or genomics-based markers are principally prognostic markers. Clinical and pathological factors such as estrogen receptor (ER) status, tumor size, nodal status, and grade are imperfect but commonly available prognostic markers. Combining these clinicopathological factors can improve estimates for prognosis, as is the case for Adjuvant! Online (AOL), a validated and widely used prognostic tool (3), or St. Gallen criteria, a risk stratification group based on consensus recommendations (4). Further improvements may be seen with genomics-based prognostic tools (5, 6) such as the MammaPrint 70 gene signature (NKI 70), the wound signature, and molecular subtypes, to name a few.Unlike prognostic markers, few therapy-predictive markers have been reported primarily because they are more difficult to identify than prognostic markers (5). This challenge arises because, if a better outcome is associated with a particular marker in a treated population, it is difficult to determine whether the marker is tracking with good prognosis (i.e., in patients without occult disease) or sensitivity to the treatment (i.e., in patients with occult disease cured by therapy). Nonetheless, prognostic markers and therapy-predictive markers are distinguishable and complementary. Consider patients with occult metastases who are treated with ADCT and cured. Although these patients may have been properly identified as having a poor prognosis by a particular prognostic marker, the accuracy of the prognostic marker is decreased because outcome has been unknowingly altered by therapy. The integration of a therapy-predictive marker will identify these treatment-sensitive patients as those with a better outcome than predicted by the prognostic marker alone. Therefore, combining a therapy-predictive marker with prognostic markers has the effect of increasing the accuracy of outcome prediction by an amount approximately equal to the benefit of the treatment, which for ADCT is approximately 5% to 10%. Importantly, the association of a therapy-predictive marker with clinical outcome principally occurs in the presence but not in the absence of treatment. For prognostic markers, an association is typically seen regardless of treatment.Previously, we described the IFN-related DNA damage resistance signature (IRDS), an experimentally derived gene-expression profile that is associated with an IFN signaling pathway and with resistance to radiation-induced DNA damage (7). Here we report the existence of an IRDS(+) and IRDS(−) state among a wide variety of primary human cancers. Targeting of IRDS genes can influence experimental resistance to chemotherapy, and a clinical classifier for IRDS status is a therapy-predictive marker of adjuvant therapy for breast cancer.     

Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy.

Fifty-five ovarian cancer patients receiving platinum drug-based chemotherapy have been studied prospectively to determine the extent of formation of the bidentate intrastrand adducts of diammineplatinum covalently attached to the N7 positions of adenosine and/or guanosine in leukocyte DNA. Data for clinical response, obtained from medical records, were then correlated with the adduct values. Patients were treated with platinum-based single-agent or combination chemotherapy containing cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum on approved experimental protocols. Adduct measurements were performed by ELISA, and disease response to therapy was assessed by standard oncologic criteria. This study comprises a total of 101 blood samples obtained after intravenous cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum infusion from 55 individuals, and in each case the highest (or "peak") adduct level for each patient was chosen for statistical analysis. Values for median adduct levels in patients grouped by complete response, partial response, and no response were 212, 193, and 62 amol of adduct per microgram of DNA, respectively. Analysis of these data by Jonckheere's test (an extension of the Mann-Whitney test) shows that higher levels of adduct formation correlates with disease response with a two-sided P value of 0.030. Of eight patients on single-agent therapy whose buffy-coat samples did not have measurable adduct levels, none responded to therapy. Analysis of these data using the exact test for trend shows that the formation of adduct at a level of 160 amol/micrograms of DNA or greater correlates with disease response with a two-sided P value of 0.032. Thus in ovarian cancer patients, the formation of the intrastrand diammineplatinum adducts in leukocyte DNA is associated with favorable disease response to cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum chemotherapy.     

Autoantibody biomarkers identified by proteomics methods distinguish ovarian cancer from non-ovarian cancer with various CA-125 levels

Purpose

CA-125 has been a valuable marker for detecting ovarian cancer, however, it is not sensitive enough to detect early-stage disease and not specific to ovarian cancer. The purpose of our study was to identify autoantibody markers that are specific to ovarian cancer regardless of CA-125 levels.

Methods

Top-down and iTRAQ quantitative proteomics methods were used to identify high-frequency autoantibodies in ovarian cancer. Protein microarrays comprising the recombinant autoantigens were screened using serum samples from various stages of ovarian cancer with diverse levels of CA-125 as well as benign and healthy controls. ROC curve and dot blot analyses were performed to validate the sensitivity and specificity of the autoantibody markers.

Results

The proteomics methodologies identified more than 60 potential high-frequency autoantibodies in ovarian cancer. Individual serum samples from ovarian cancer stages I–IV compared to control samples that were screened on a microarray containing native recombinant autoantigens revealed a panel of stage I high-frequency autoantibodies. Preliminary ROC curve and dot blot analyses performed with the ovarian cancer samples showed higher specificity and sensitivity as compared to CA-125. Three autoantibody markers exhibited higher specificity in various stages of ovarian cancer with low and normal CA-125 levels.

Conclusions

Proteomics technologies are suitable for the identification of protein biomarkers and also the identification of autoantibody biomarkers when combined with protein microarray screening. Using native recombinant autoantigen arrays to screen autoantibody markers, it is possible to identify markers with higher sensitivity and specificity than CA-125 that are relevant to early detection of ovarian cancer.     

Poor outcome of elderly patients with platinum-sensitive recurrent ovarian cancer: Results from the SOCRATES retrospective study

Background

Elderly patients with ovarian carcinoma have a poorer prognosis compared with their younger counterpart, and this depends in most cases on undertreatment. The aim of this study was to evaluate, retrospectively, the pattern of care and the prognosis of elderly patients with platinum-sensitive recurrent ovarian cancer. The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000-2002 in 37 Italian centres. Data were collected between April and September 2005.

Patients and methods

Patients with recurrent ovarian cancer with >6 months of platinum free interval were considered eligible. Four-hundred-ninety-three patient files were collected and 425 were considered eligible and analyzed. Ninety-four patients with age ≥70 years and 331 patients with age <70 years were analyzed.

Results

Recurrence free interval (RFI), PS, and number of disease sites were similar among the two groups. A lower proportion of elderly patients underwent secondary cytoreduction (8.9% compared to 23.9%; p = 0.0018). The mean number of chemotherapy lines received for recurrence was 2.7 and 2.5 in young and aged patients, respectively. Elderly patients received more frequently at second line single agent platinum than platinum-combination therapy or other non-platinum chemotherapy. The response rate to the second line chemotherapy was higher in younger patients than in the elderly population (CR + PR, younger: 67.2%; elderly: 46.5%; p = 0.0004). Median overall survival from recurrence was 30.7 months in the younger patients and 23.6 months in the elderly group (p = 0.0037). At multivariate analysis, number of disease sites (>1 vs. 1), performance status at recurrence (2-3 vs. 0-1), RFI (6-12 months vs. >12 months), age at recurrence, were independently associated with survival.

Conclusion

Elderly patients with platinum-sensitive recurrent ovarian cancer receive less surgery and chemotherapy. Response to chemotherapy is better in younger patients. Age is an unfavourable factor independently associated to a worst prognosis.     

DNA microarrays: technology and new insights in oncology

INTRODUCTION: Large-scale genomic studies based on DNA microarrays improve our understanding of the pathophysiology of cancers. The use of these research findings to improve diagnosis, prognosis and treatment is the current challenge of research in genomics. EXEGESIS: The article briefly describes the DNA microarrays technology and use in oncology and underlines the steps required to translate research findings of correlations between gene expression and type of cancer, outcome or response to chemotherapy into robust clinical tools. CONCLUSION: Genomic technologies available today are sufficient to develop useful molecular markers for individual patient management.     

Identification of differentially expressed proteins in ovarian cancer using high-density protein microarrays

Ovarian cancer is a leading cause of deaths, yet many aspects of the biology of the disease and a routine means of its detection are lacking. We have used protein microarrays and autoantibodies from cancer patients to identify proteins that are aberrantly expressed in ovarian tissue. Sera from 30 cancer patients and 30 healthy individuals were used to probe microarrays containing 5,005 human proteins. Ninety-four antigens were identified that exhibited enhanced reactivity from sera in cancer patients relative to control sera. The differential reactivity of four antigens was tested by using immunoblot analysis and tissue microarrays. Lamin A/C, SSRP1, and RALBP1 were found to exhibit increased expression in the cancer tissue relative to controls. The combined signals from multiple antigens proved to be a robust test to identify cancerous ovarian tissue. These antigens were also reactive with tissue from other types of cancer and thus are not specific to ovarian cancer. Overall our studies identified candidate tissue marker proteins for ovarian cancer and demonstrate that protein microarrays provide a powerful approach to identify proteins aberrantly expressed in disease states.