Copy number changes of 4-gene set may predict early relapse in advanced epithelial ovarian cancer after initial platinum-paclitaxel chemotherapy

For advanced epithelial ovarian cancer (EOC), time to recurrence (TTR) is an important indicator to gauge the therapeutic efficacy of postoperative adjuvant chemotherapy. Our objective was to determine the genes that could potentially distinguish patients with short versus long TTR after initial administration of platinum-paclitaxel combination chemotherapy in advanced EOC. Tumor samples of 159 patients were obtained during the primary cytoreduction. Array comparative genomic hybridization (CGH) was carried with genomic DNA from 17 EOC samples (8 with TTR > 15 months and 9 with TTR ≤ 6 months) to screen candidate gene set, copy-number changes (CNC) of which were significantly different between early and late relapse cases. Seventeen candidate genes were identified by array CGH. The analysis of consistency between real-time PCR and array CGH revealed that 4 genes displayed consistent results, namely GSTT1, ISG20L1, STARD5 and FREM1. In a 142-case validation set, CNC of 4 candidate genes was evaluated and verified by real-time PCR. Sixty five point five percent of the patients were correctly divided into early (TTR ≤ 10 months) and late (TTR > 10 months) recurrent group by CNC of the 4 genes using discriminant analysis. The results showed that CNC of 4-gene set could potentially determine early (TTR ≤ 10 months) or late relapse (TTR > 10 months) after initial platinum-paclitaxel combination chemotherapy in advanced EOC.     

上皮性卵巢癌复发的影响因素分析

背景与目的:中晚期上皮性卵巢癌复发率较高,生存率低。在没有可靠的早期诊断技术的情况下,了解其复发的影响因素对于预后的判断和指导治疗具有非常重要的意义。本文旨在探讨上皮性卵巢癌复发的影响因素。方法:109例上皮性卵巢癌,对可能导致病人复发的影响因素:年龄,病理类型,临床分期,新辅助化疗,术后化疗方案和化疗疗程,初次手术治疗情况;以及手术残留癌灶大小,用Logistic回归方法进行回顾性总结和分析。结果:109例患者中复发36例,复发率为33.0％,中位复发时间19个月;109例病人总的5年生存率为62.7％,复发病人5年生存率43.3％;盆腔复发病人的5年生存率为50.1％,盆腔外复发病人的5年生存率36.1％,二者相比较无统计学意义(P>0.05)。单因素分析分别显示粘液性腺癌和临床分期为Ⅰ期的复发风险较低(回归系数β=1.565和-1.799,P=0.0120和0.026);而化疗疗程>8个疗程的病人复发风险明显高于1～4疗程和6～8疗程 的病人(回归系数β=-3.591和-1.500,P<0.001和=0.038)。多因素分析显示病理类型、临床分期和术后化疗疗程数是影响卵巢癌治疗后复发的独立危险因素(RR=3.473,4.713和6.140,P<0.05)。结论:临床分期是影响复发的显著因素,早期诊断对于降低卵巢癌复发率十分重要。合理的化疗计划对于卵巢癌的治疗是必要的,     

Gene expression patterns of chemoresistant and chemosensitive serous epithelial ovarian tumors with possible predictive value in response to initial chemotherapy

Chemotherapy (CT) resistance in ovarian cancer is broad and encompasses diverse, unrelated drugs, suggesting more than one mechanism of resistance. We aimed to analyze the gene expression patterns in primary serous epithelial ovarian cancer (EOC) samples displaying different responses to first-line CT in an attempt to identify specific molecular signatures associated with response to CT. Initially, the expression profiles of 15 chemoresistant serous EOC tumors [time to recurrence (TTR) or =30 months) were independently analyzed which allowed the identification of specific sets of differentially expressed genes that might be functionally implicated in the evolution of the chemoresistant or the chemosensitive phenotype. Our data suggest that the intrinsic chemoresistance in serous EOC cells may be attributed to the combined action of different molecular mechanisms and factors linked with drug influx and efflux and cell proliferation, as possible implications of other molecular events including altered metabolism, apoptosis and inflammation cannot be excluded. Next, gene expression comparison using hierarchical clustering clearly distinguished chemosensitive and chemoresistant tumors from the 25 serous EOC samples (training set), and consecutive class prediction analysis was used to develop a 43-gene classifier that was further validated in an independent cohort of 15 serous EOC patients and 2 patients with other ovarian cancer histotypes (test set). The 43-gene predictor set properly classified serous EOC patients at high risk for early (< or =22 months) versus late (>22 months) relapse after initial CT. Thus, gene expression array technology can effectively classify serous EOC tumors according to CT response. The proposed 43-gene model needs further validation.     

铂类化疗敏感型卵巢上皮癌复发的影响因素

背景与目的:卵巢癌患者中对铂类化疗敏感者较耐药者预后好,但是铂类化疗敏感型卵巢上皮癌患者中仍有较高的复发率,从而影响此类患者的预后。本研究旨在总结对铂类化疗敏感型卵巢上皮癌患者的临床特点,探讨影响其复发的因素。方法:回顾性分析和总结1993～1999年中山大学肿瘤防治中心收治的90例临床完全缓解超过6个月以上的对铂类化疗敏感型卵巢上皮癌患者复发的影响因素。复发相关的单因素分析采用χ2检验,多因素分析采用Cox模型。结果:90例卵巢上皮癌患者中出现复发者36例,复发率为40.0%,中位复发时间20个月。复发的部位以盆腔最多,占50.0%(18/36)。90例患者总的3年、5年生存率分别为79.6%、69.5%。36例复发患者3年、5年生存率分别为62.3%、39.6%。单因素分析显示铂类化疗敏感型卵巢上皮癌中FIGO分期早、无新辅助化疗、粘液性癌者复发风险低(P=0.001,P=0.002和P=0.025)。经Cox多因素分析显示仅FIGO分期是肿瘤复发的独立危险因子(RR=1.771,P=0.003)。术后采用CBP和铂类其它组合的方案化疗对铂类化疗敏感型卵巢上皮癌复发的影响差异无显著性,过多疗程的术后化疗并不能减少复发。结论:FIGO分期是影响铂类化疗敏感型卵巢上皮癌复发的显著因素,早期诊断对于降低复发十分重要。     

The prognostic and predictive role of 21-gene recurrence scores in hormone receptor-positive early-stage breast cancer

Over the past two decades, gene expression profiling of breast cancer has emerged as an important tool in early-stage breast cancer management. The approach provides important information on underlying biological mechanisms, breast cancer classification, future risk potential of developing recurrent metastatic disease, and provides beneficial clues for adjuvant chemotherapy in hormone receptor (HR) positive breast cancer. Of the commercially available genomic tests for breast cancer, the prognostic and predictive value of 21-gene recurrence score tests have been validated using both retrospective data and prospective clinical trials. In this paper, we reviewed the current evidence on 21-gene expression profiles for HR-positive HER2-negative early-stage breast cancer management. We show that current evidence supports endocrine therapy alone as an appropriate adjuvant systemic therapy for approximately 70% of women with HR-positive, HER2-negative, node-negative breast cancer. Evolving evidence also suggests that 21-gene recurrence scores have predictive values for node-positive breast cancer and that chemotherapy can be avoided in more than half of women with nodes 1 to 3 positive HR-positive breast cancer. Furthermore, retrospective data also supports the predictive role of 21-gene recurrence scores for adjuvant radiation therapy. A prospective trial in this area is ongoing.     

International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer

BACKGROUND: The question of whether platinum-based adjuvant chemotherapy can improve outcomes in patients with early-stage epithelial ovarian cancer is an important one. We carried out a multicenter, open randomized trial to determine whether adjuvant chemotherapy would improve overall survival and prolong recurrence-free survival in women with early-stage epithelial ovarian cancer. METHODS: Between August 1991 and January 2000, 477 patients in 84 centers in five countries were randomly assigned to receive either adjuvant chemotherapy immediately following surgery (n = 241) or no adjuvant chemotherapy until clinically indicated (n = 236). Kaplan-Meier curves of overall survival and recurrence-free survival were compared using the Mantel-Cox version of the log-rank test. All statistical tests were two-sided. RESULTS: Women who received adjuvant chemotherapy had better overall survival than women who did not (hazard ratio [HR] of 0.66, 95% confidence interval [CI] = 0.45 to 0.97; P =.03). These results translate into 5-year survival figures of 70% for women who did not receive adjuvant chemotherapy and 79% for women who did receive adjuvant chemotherapy, a difference of 9% (95% CI = 1% to 15%). Adjuvant chemotherapy also improved recurrence-free survival (HR = 0.65; 95% CI = 0.46 to 0.91; P =.01). These results translate into 5-year recurrence-free survival figures of 62% for women who did not receive adjuvant chemotherapy and 73% for women who did receive adjuvant chemotherapy, a difference of 11% (95% CI = 3% to 18%). CONCLUSION: These results suggest that platinum-based adjuvant chemotherapy improves survival and delays recurrence in patients with early-stage ovarian cancer.     

Adjuvant chemotherapy with carboplatin and taxane compared with single drug carboplatin in early stage epithelial ovarian carcinoma

The objective of the present study was to compare recurrence-free survival (RFS) in early stages (FIGO stages I-II) of epithelial ovarian cancer after adjuvant chemotherapy with carboplatin and a taxane (113 patients) and with carboplatin alone (27 patients). The distribution of clinical and pathological prognostic factors as well as type of primary surgery were comparable in the two groups. Recurrence rate was 21% and RFS was 79% in the series of patients treated with taxane-based chemotherapy and 19% and 81%, respectively, in the series of patients who received single drug carboplatin. Thus, no significant differences were recorded. The major toxicities in the present study were myelosuppression (46%) and neuro-toxicity (26%). Neuro-toxicity was more frequently (P=0.007) recorded and of higher grade (P=0.011) for patients in the carboplatin-taxane series compared with patients in the carboplatin series. RFS for patients in FIGO-stage I was 85% and for patients in FIGO-stage II only 47%. In a multivariate logistic regression analysis of predictive factors for tumor recurrence in the complete series (n=140) the FIGO stage was the only independent and significant (P=0.0006) predictive factor with an odds ratio of 6.4 (95% CI: 2.2-18.9) for stage II versus IA-C. Age, tumor grade and type of adjuvant chemotherapy (+/- taxane) were not significant predictive factors. In the present study, although based on a limited number of patients, we could not find any improvement in recurrence rate or recurrence-free survival for patients treated with a carboplatin-taxane combination regimen compared with patients treated with carboplatin monotherapy. The spectrum of side effects was also in favor of the monotherapy regimen. Further, larger randomized studies are needed to give a final and fully conclusive answer to this question.     

A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer

Standard chemotherapy for advanced epithelial ovarian cancer is a combination of platinum-paclitaxel. One strategy to improve the outcome for patients is to add other agents to standard therapy. Doxil is active in relapsed disease and has a response rate of 25% in platinum-resistant relapsed disease. A dose finding study of doxil-carboplatin-paclitaxel was therefore undertaken in women receiving first-line therapy. Thirty-one women with epithelial ovarian cancer or mixed Mullerian tumours of the ovary were enrolled. The doses of carboplatin, paclitaxel and doxil were as follows: carboplatin AUC 5 and 6; paclitaxel, 135 and 175 mg m(-2); doxil 20, 30, 40 and 50 mg m(-2). Schedules examined included treatment cycles of 21 and 28 days, and an alternating schedule of carboplatin-paclitaxel (q 21) with doxil being administered every other course (q 42). The dose-limiting toxicities were found to be neutropenia, stomatitis and palmar plantar syndrome and the maximum tolerated dose was defined as; carboplatin AUC 5, paclitaxel 175 mg m(-2) and doxil 30 mg m(-2) q 21. Reducing the paclitaxel dose to 135 mg m(-2) did not allow the doxil dose to be increased. Delivering doxil on alternate cycles at doses of 40 and 50 mg m(-2) also resulted in dose-limiting toxicities. The recommended doses for phase II/III trials are carboplatin AUC 6, paclitaxel 175 mg m(-2), doxil 30 mg m(-2) q 28 or carboplatin AUC 5, paclitaxel 175 mg m(-2), doxil 20 mg m(-2) q 21. Grade 3/4 haematologic toxicity was common at the recommended phase II doses but was short lived and not clinically important and non-haematologic toxicities were generally mild and consisted of nausea, paraesthesiae, stomatitis and palmar plantar syndrome.     

Does Human Epididymis Protein 4 (HE4) Have a Role in Prediction of Recurrent Epithelial Ovarian Cancer

Background: Despite the fact that ovarian cancer is the seventh most common cancer in women worldwide and the fth leading cause of cancer death, It is the most common cause of death due to reproductive cancers in Thailand where epithelial ovarian cancer (EOC) is commonly found. According to a Thai statistical analysis in 2010 by the Department of Medical Services, epithelial ovarian cancer was the sixth most common cancer in Thailand from 2001 to 2003.The incidence of 5.1 per 100,000 women per year. Human epididymis protein 4 (HE4) is a novo diagnostic tumor marker for EOC. The combination of HE4 and carcinoma antigen 125 (CA 125) is a tool for detecting epithelial ovarian cancer (EOC) better than using CA 125 alone. Therefore, the researcher is interested in HE4 does have a role to predict recurrent epithelial ovarian cancer. Materials and Methods: The patients who had complete response after diagnosed with epithelial ovarian cancer by pathology, FIGO stage 3 or more had been treated through surgery and chemotherapy at the Sunpasitthiprasong Hospital from June 2014 until March 2016. The patients were followed up every three months, using tumor marker (CA 125, HE4,Carcinoma antigen 19-9) together with other checkup methods, such as rectovaginal examination, CXR every year and other imaging as indication. Afterwards, the data was analyzed for the ability of HE4 to detect recurrence of epithelial ovarian cancer. Results: In 47 patients in this study follow-up for 22 months after complete response treatment from surgery and chemotherapy in epithelial ovarian cancer, 23 had recurrent disease and HE4 titer rising .The patients with recurrent epithelial ovarian cancer demonstrated high levels of both HE4 and CA125 with sensitivity of 91.3% and 52.7% respectively, speci city of 87.5% and 95.6% and positive predictive values of 87.5% and 85.7% . HE4 can predict recurrent epithelial ovarian cancer (p-value=0.02242). Comparing HE4 and CA125 in predicting recurrent epithelial ovarian cancer HE4 had more potential than CA125 (p-value =0.8314). Conclusions: The present study showed HE4 to have a role in predicting recurrent epithelial ovarian cancer and HE4 is potentially better than CA125 as a marker for this purpose.     

影响上皮性卵巢癌复发患者预后相关临床病理因素分析

目的分析影响上皮性卵巢癌(epithelial ovarian cancer,EOC)复发患者预后的相关临床病理因素。方法采用Kaplan-meier生存率曲线,Log rank检验和Cox模型多因素回归分析法对92例临床病理及随访资料完整的复发癌患者进行影响其预后的相关因素分析。结果(1)92例复发上皮性卵巢癌临床病例的总体中位生存时间是18月(95%CI:16.052~19.948);(2) Kaplan-Meier单因素分析提示,FIGO分期、复发距离末次化疗时间、复发部位、最大复发病灶、复发后伴有腹水、CA125升高、复发后二次肿瘤细胞减灭术、再次治疗化疗方案是影响复发EOC患者的重要预后因素(P<0.1)。而年龄、肿瘤细胞分级、初次治疗方案与预后无关(P>0.1);(3)Cox回归分析结果显独示,复发后再次治疗化疗方案、最大复发病灶大小、复发部位是影响患者预后的独立危险因素。结论 多个临床病理因素影响复发上皮性卵巢癌预后,其中复发后再次治疗化疗方案、最大复发病灶大小、复发部位是影响患者预后的独立危险因素。     

Recommendations from the European Commission Initiative on Breast Cancer for multigene testing to guide the use of adjuvant chemotherapy in patients with early breast cancer,hormone receptor positive,HER-2 negative

Background Predicting the risk of recurrence and response to chemotherapy in women with early breast cancer is crucial to optimise adjuvant treatment. Despite the common practice of using multigene tests to predict recurrence, existing recommendations are inconsistent. Our aim was to formulate healthcare recommendations for the question “Should multigene tests be used in women who have early invasive breast cancer, hormone receptor-positive, HER2-negative, to guide the use of adjuvant chemotherapy?”Methods The European Commission Initiative on Breast Cancer (ECIBC) Guidelines Development Group (GDG), a multidisciplinary guideline panel including experts and three patients, developed recommendations informed by systematic reviews of the evidence. Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision frameworks were used. Four multigene tests were evaluated: the 21-gene recurrence score (21-RS), the 70-gene signature (70-GS), the PAM50 risk of recurrence score (PAM50-RORS), and the 12-gene molecular score (12-MS).Results Five studies (2 marker-based design RCTs, two treatment interaction design RCTs and 1 pooled individual data analysis from observational studies) were included; no eligible studies on PAM50-RORS or 12-MS were identified and the GDG did not formulate recommendations for these tests.Conclusions The ECIBC GDG suggests the use of the 21-RS for lymph node-negative women (conditional recommendation, very low certainty of evidence), recognising that benefits are probably larger in women at high risk of recurrence based on clinical characteristics. The ECIBC GDG suggests the use of the 70-GS for women at high clinical risk (conditional recommendation, low certainty of evidence), and recommends not using 70-GS in women at low clinical risk (strong recommendation, low certainty of evidence).Subject terms: Prognostic markers, Breast cancer     

Prognostic value of biologic subtype and the 21-gene recurrence score relative to local recurrence after breast conservation treatment with radiation for early stage breast carcinoma: results from the Eastern Cooperative Oncology Group E2197 study

The present study was performed to evaluate the significance of biologic subtype and 21-gene recurrence score relative to local recurrence and local-regional recurrence after breast conservation treatment with radiation. Eastern Cooperative Oncology Group E2197 was a prospective randomized clinical trial that compared two adjuvant systemic chemotherapy regimens for patients with operable breast carcinoma with 1-3 positive lymph nodes or negative lymph nodes with tumor size >1.0 cm. The study population was a subset of 388 patients with known 21-gene recurrence score and treated with breast conservation surgery, systemic chemotherapy, and definitive radiation treatment. Median follow-up was 9.7 years (range = 3.7-11.6 years). The 10-year rates of local recurrence and local-regional recurrence were 5.4 % and 6.6 %, respectively. Neither biologic subtype nor 21-gene Recurrence Score was associated with local recurrence or local-regional recurrence on univariate or multivariate analyses (all P ≥ 0.12). The 10-year rates of local recurrence were 4.9 % for hormone receptor positive, HER2-negative tumors, 6.0 % for triple negative tumors, and 6.4 % for HER2-positive tumors (P = 0.76), and the 10-year rates of local-regional recurrence were 6.3, 6.9, and 7.2 %, respectively (P = 0.79). For hormone receptor-positive tumors, the 10-year rates of local recurrence were 3.2, 2.9, and 10.1 % for low, intermediate, and high 21-gene recurrence score, respectively (P = 0.17), and the 10-year rates of local-regional recurrence were 3.8, 5.1, and 12.0 %, respectively (P = 0.12). For hormone receptor-positive tumors, the 21-gene recurrence score evaluated as a continuous variable was significant for local-regional recurrence (hazard ratio 2.66; P = 0.03). The 10-year rates of local recurrence and local-regional recurrence were reasonably low in all subsets of patients. Neither biologic subtype nor 21-gene recurrence score should preclude breast conservation treatment with radiation.     

Trial assessing individualized options for treatment for breast cancer: the TAILORx trial

Novel genetic profiling tests of breast cancer tissue have been shown to be prognostic for overall survival and predictive of local and distant rates of recurrence in breast cancer patients. One of these tests, Oncotype DXtrade mark, is a diagnostic test comprised of a 21-gene assay applied to paraffin-embedded breast cancer tissue, which allows physicians to predict subgroups of hormone-receptor-positive, node-negative patients who may benefit from hormonal therapy alone or require adjuvant chemotherapy to attain the best survival outcome. The results of the assay are converted to a recurrence score (0-100) that has been found to be predictive of 10- and 15-year local and distant recurrence in node-negative, estrogen-receptor-positive breast cancer patients. Previous studies have shown that patients with high recurrence scores benefit from adjuvant chemotherapy, whereas patients with low recurrence scores do not. To evaluate the ability to guide treatment decisions in the group with a mid-range recurrence score, the North American Cooperative Groups developed the Trial Assessing IndiviuaLized Options for Treatment for breast cancer, a randomized trial of chemotherapy followed by hormonal therapy versus hormonal therapy alone on invasive disease-free survival-ductal carcinoma in situ (IDFS-DCIS) survival in women with node-negative, estrogen-receptor-positive breast cancer with a recurrence score of 11-25. The study was initiated in May 2006 and approximately 4500 patients will be randomized. This article describes the rationale, methodology, statistical ana-lysis and implications of the results on clinical practice.     

Cyclin E-associated kinase activity predicts response to platinum-based chemotherapy.

PURPOSE: The role of cyclin E as a predictive marker of response to chemotherapy remains unknown. We have previously shown that deregulation of cyclin E in an ovarian tumor cell line model enhances cyclin E-associated kinase activity and sensitizes tumor cells to cisplatinum. We hypothesized that cyclin E deregulation would predict for responsiveness to platinum-based regimens in ovarian cancer patients. EXPERIMENTAL DESIGN: Patients who met the following criteria were retrospectively identified from the institutional tumor bank records: (a) high-grade ovarian epithelial malignancy, (b) stage III/stage IV disease, (c) optimally debulked, (d) completed platinum-based therapy. Tumor samples were analyzed for cyclin E, p21, and p27 by Western blot analysis and assessed for cyclin E-associated kinase activity. RESULTS: Seventy-five patients, who met the study criteria, were identified. Cyclin E protein levels did not correlate with cyclin E-cdk2 kinase activity (Spearman's rho, 0.07; P = 0.58). Cyclin E-associated kinase activity was the only significant predictive marker for response to platinum-based therapy, with higher response rates seen in patients with higher levels of activity (P = 0.045). Cyclin E protein levels did not predict for platinum sensitivity (P = 0.20). In contrast, cyclin E protein levels, but not cyclin E-associated kinase activity, was a significant predictor for freedom from recurrence (P = 0.01 and P = 0.25, respectively). CONCLUSIONS: Cyclin E overexpression and cyclin E-associated kinase activity have distinct roles in predicting for response to chemotherapy and outcome in ovarian cancer patients. These results suggest a compartmentalization of cyclin E functions in the oncogenic process.     

Prognostic factors for high-risk early-stage epithelial ovarian cancer: a Gynecologic Oncology Group study

BACKGROUND: The purpose was to identify the factors predictive of recurrence and survival in patients with high-risk (stage I, grade 3; stage IC, stage II, or clear cell) epithelial ovarian cancer after adjuvant therapy. METHODS: Data was extracted from patients who underwent primary surgery followed by adjuvant therapy in 2 randomized trials by the Gynecologic Oncology Group (Protocols 95 and 157). Kaplan-Meier survival estimates and Cox proportional hazards model adjusted for covariates were used for analyses. RESULTS: Of 506 patients (median age = 56.2 years), 347 (68.6%) had stage I and 159 (31.4%) had stage II cancers. The 5-year recurrence-free (RFS) and overall survivals (OS) were 75.5% and 81.7%, respectively. On multivariate analysis, older age, higher stage, higher grade, and malignant cytology were independent prognostic factors predictive for recurrence and poorer survival. The risk of recurrence was higher for those >/=60 versus < 60 years (hazards ratio [HR] = 1.57, 95% confidence interval [CI], 1.12-2.19), stage II (stage II: HR = 2.70, 95% CI, 1.41-5.16) versus stage IA or IB, grade 2 (HR = 1.84, 95% CI, 1.04-3.27) and grade 3 (HR = 2.47, 95% CI, 1.39-4.37) versus grade 1, and positive versus negative cytology (HR = 1.72, 95% CI, 1.21-2.45). By using these factors in a prognostic index, those with low-risk (no or 1 risk factor), intermediate-risk (2 factors), and high-risk (3-4 risk factors) disease had survivals of 88%, 82%, and 75%, respectively (P < .05). CONCLUSIONS: Age, stage, grade, and cytology are important prognostic factors in high-risk early-stage epithelial ovarian cancer. This information may be used in the design of future clinical trials.     

Adjuvant treatment for early epithelial ovarian cancer: Results of two randomised clinical trials comparing cisplatin to no further treatment or chromic phosphate (32P)

BACKGROUND: From 1983 to 1990, 271 consecutive patients with stage I ovariancancer entered two randomised trials, aimed at assessing therole of adjuvant chemotherapy after radical surgery in earlystages of ovarian cancer.Trial I compared cisplatin (50 mg/m²with repeated courses every 28 days for 6 cycles) to no furthertherapy in F.I.G.O.stage la & b Grade U-IH patients; trialII compared cisplatin (same dose and schedule) to ³²P in Ian& bii and Ic patients METHODS: Both studies were multicentric and centrally randomized. Treatmentwas allocated by phone and stratified by center. All patientssatisfying major eligibility criteria (histological diagnosisof ovarian carcinoma, correct F.I.G.O. stage and grade, no previousneoplasms) were analysed according to treatment allocated byrandomisation. RESULTS: With a median observation time of 16 months, cisplatin significantlyreduced the relapse rate by 65% (HR = 0.35; 95% CI = 0.14–0.89,p = 0.028; Cox Model) in trial I and 61% (HR = 0.39; 95% CI= 0.19–0.77, p = 0.007; Cox Model) in trial II. Survivalwas not significantly different (trial I – Kaplan-Meieroverall 5-year survival: cisplatin = 88%, control = 82%, HR= 1.15; 95% CI = 0.44 – 2.98; p = 0.773; Cox Model); trialII – overall 5-year survival: cisplatin = 81%, 32P = 79%,HR = 0.72; 95% CI = 0.37–1.43; p = 0.354; Cox model).In both studies the risk of dying after relapse increased forpatients originally randomized to the cisplatin arms: in trialI, 6 of 7 patients in the cisplatin relapsed arm and died oftumor compared with 8 of 14 patients in the control arm. Intrial II, 11 of 12 patients on cisplatin, and 18 of 26 on 32Psuccumbed to tumor recurrence. CONCLUSION: Adjuvant cisplatin treatment in early ovarian cancer significantlyprevents relapse in comparison to ³²P in Stage IC patients orto no immediate treatment in earlier Stage women. The impactof cisplatin adjuvant treatment on survival remains, however,unclear. early ovarian neoplasm, randomised trial, chemotherapy     

Androgen mediation of thrombocytosis in epithelial ovarian cancer biology.

PURPOSE: Preoperative thrombocytosis (platelet count > 400 x 10(9)/L) at initial exploration for epithelial ovarian carcinoma is associated with decreased surgical cytoreducibility and poor survival. Platelets express androgen receptor (AR), which contains a polymorphic CAG trinucleotide repeat sequence of which the length inversely correlates with AR transactivation function. We hypothesized that androgen-mediated thrombocytosis promotes aggressive ovarian cancer biology. EXPERIMENTAL DESIGN: Sixty-three patients with epithelial ovarian carcinoma underwent genotype analysis of the CAG repeat polymorphism in AR. Medical records were reviewed to assess preoperative thrombocytosis, surgical findings, and survival. Data were examined using the Fisher's exact, logistic regression, and Kaplan-Meier analyses. RESULTS: AR CAG repeat lengths ranged from 8 to 27, with a median of 23. Fifteen of 63 patients (23.8%) showed preoperative thrombocytosis. Short AR allelotype (< or = 20 CAG repeats) was associated with a higher incidence of thrombocytosis (P = 0.04). The combination of short AR allelotype and thrombocytosis was the only significant factor that predicted inability to achieve optimal surgical cytoreduction (P = 0.02). Women with short AR allelotype and thrombocytosis showed statistically decreased progression-free survival (13 versus 37 months, P = 0.01) and overall survival (37 versus 65 months, P = 0.02) when compared with women with long AR allelotype and normal platelet counts. On multivariate analyses, suboptimal cytoreduction was the only significant factor predictive of disease-specific overall survival (P = 0.0002) but the combination of short AR allelotype and thrombocytosis approached statistical significance (P = 0.08). CONCLUSIONS: Androgen modulation of thrombocytosis may promote aggressive epithelial ovarian cancer biology.     

Automated quantitative analysis of DCC tumor suppressor protein in ovarian cancer tissue microarray shows association with beta-catenin levels and outcome in patients with epithelial ovarian cancer.

BACKGROUND: The deleted in colorectal cancer (DCC) protein, the product of DCC tumor suppressor gene, is frequently altered in cancer. Preclinical data demonstrate that DCC regulates beta-catenin levels. Here, we sought to determine the association of DCC with beta-catenin protein levels, clinicopathological parameters and patient outcome in ovarian cancer using a method of in situ compartmentalized protein analysis. METHODS: A tissue array composed of 150 advanced-stage ovarian cancers, treated with surgical debulking and platinum-paclitaxel (Taxol) combination chemotherapy, was constructed. For evaluation of protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). RESULTS: One hundred and twelve patients (74%) had sufficient tissue for AQUA. The median follow-up time for the entire cohort was 33 months. Patients with low nuclear DCC expression had a 3-year progression-free survival (PFS) rate of 0% compared with 33% of those with high DCC expression (P = 0.0067). In multivariate analysis, low nuclear DCC expression level retained its prognostic significance for PFS. Between DCC and beta-catenin, a significant relationship was found, where tumors with low DCC had low beta-catenin and vice versa (P = 0.003). CONCLUSIONS: Low nuclear DCC levels predict for poor patient outcome in epithelial ovarian cancer. DCC may exert its antitumor function, in part, through regulation of beta-catenin levels.     

BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy.

PURPOSE: We investigated whether BRCA1 mRNA expression levels may represent a biomarker of survival in sporadic epithelial ovarian cancer following chemotherapy treatment. EXPERIMENTAL DESIGN: The effect of loss of BRCA1 expression on chemotherapy response in ovarian cancer was measured in vitro using dose inhibition assays and Annexin V flow cytometry. Univariate and multivariate analyses were done to evaluate the relationship between BRCA1 mRNA expression levels and survival after chemotherapy treatment in 70 fresh frozen ovarian tumors. RESULTS: We show that inhibition of endogenous BRCA1 expression in ovarian cancer cell lines results in increased sensitivity to platinum therapy and decreased sensitivity to antimicrotubule agents. In addition, we show that patients with low/intermediate levels of BRCA1 mRNA have a significantly improved overall survival following treatment with platinum-based chemotherapy in comparison with patients with high levels of BRCA1 mRNA (57.2 versus 18.2 months; P = 0.0017; hazard ratio, 2.9). Furthermore, overall median survival for higher-BRCA1-expressing patients was found to increase following taxane-containing chemotherapy (23.0 versus 18.2 months; P = 0.12; hazard ratio, 0.53). CONCLUSIONS: We provide evidence to support a role for BRCA1 mRNA expression as a predictive marker of survival in sporadic epithelial ovarian cancer.