Molecular prognostic factors in early-stage cervical adenocarcinoma.

Within the past years the proportion of cervical adenocarcinomas has increased, however, there is a shortage of data regarding immunohistochemical and molecular features and their prognostic relevance in early-stage cervical adenocarcinoma (esCAC). Aim of the present study was to evaluate molecular prognostic factors in esCAC patients treated with primary surgery. Analyses of surgical specimens in 59 patients with esCAC were performed on fixed paraffin-embedded sections of tumour tissue. Tumour tissue sections were routinely stained with hematoxylin and eosin followed by microscopic examination. Immunohistochemical analyses (IHC) were performed on paraffin-embedded section. Flow cytometry (FCM) analysis of paraffin-embedded tumor tissue was performed using flow cytometer FACSCalibur equipped with argon laser. DNA histogram analysis was performed with ModFit application. Treatment effectiveness was evaluated using overall 5-year survival. Survival probability was estimated using the Kaplan-Meier method. Overall survival rate estimated using Kaplan-Meier method was 74.6%. Among the IHC and FCM features univariate analysis showed statistical significance of nm23-H1 gene expression and total S-phase fraction ≤ 11.9% (S-TOT). In multi- variate analysis LVSI and parametrial involvement had significant, negative impact on survival (HR = 8.04, p < 0.003 and HR = 4.03, p < 0.017, respectively). However, none of the tested IHC and FCM features had any influence on overall 5-year survival.

Prognostic factors in Polish patients with BRCA1-dependent ovarian cancer.

BACKGROUND: Treatment outcomes appear to be better for ovarian cancer (OC) patients carrying the BRCA1/2 germline mutation than for patients with sporadic OC. However, most published data are for North American, British and Jewish populations. There have been very few studies on treatment outcomes in Central and Eastern European patients with OC. The aim of this study was to analyse prognostic factors in Polish patients with BRCA1-dependent OC (BRCA1-OC). METHODS: The records of patients with OC treated with surgery and chemotherapy at the Centre of Oncology in Kraków, Poland, between 2004 and 2009 were reviewed. Based on family history, a group of 249 consecutive patients fulfilling the criteria for risk of hereditary OC were selected and tested for the germline BRCA1 mutation. Response to combination therapy (surgery and chemotherapy) in the BRCA1-OC group was assessed based on clinical examination, imaging and serum CA125. RESULTS: Germline BRCA1 mutations were detected in 69 of the 249 patients, but three of these patients failed to complete the study. Finally, 66 patients with BRCA1-OC were included in the study group. The median age of the study patients was 49.5 years. All had undergone primary or interval cytoreductive surgery and chemotherapy. Progression occurred in 48 (72.7 %) of the 66 patients and median time to progression was 20 months. The 5-year overall survival rate in was 43.9 % and median survival time was 32.3 months. On multivariate analysis, the endometrial subtype of OC and serum CA125 < 12.5 U/ml at the end of treatment were independent, positive prognostic factors for 5-year overall survival. CONCLUSION: Prognostic factors for favourable treatment outcomes in Polish patients with BRCA1-OC do not appear to differ from those in patients with sporadic OC. The incidence of the endometrial subtype of OC was relatively high (34.9 %) among women in the study. This was unexpected and has not been reported previously. This subtype of OC was an independent prognostic factor for favourable treatment outcomes.

Comparison of effectiveness of treatment of patients with sporadic and germline BRCA1-related ovarian cancer.

OBJECTIVES: Numerous reports suggest that the clinical course of ovarian cancer (OC) in BRCA, including BRCA1, mutation carriers (BRCA1-OC) is different than in patients with sporadic ovarian cancer (SOC). Most of the authors indicate more fa-vourable treatment results in patients with BRCA1-OC. The aim of the study was to compare the effectiveness of treatment of patients with advanced-stage (FIGO III/IV) SOC and BRCA1-OC. MATERIAL AND METHODS: Between 2004 and 2009, 957 OC patients were treated in Cracow Branch of Cancer Center, M. Sklodowska-Curie Memorial Institute, Poland. Germline BRCA1 mutation was found in 66 patients. To compare the effective-ness of treatment, the group of 47 advanced-stage BRCA1-OC patients was matched with the group of 47 advanced-stage SOC patients. Pairs of patients were matched in terms of the most important prognostic factors, i.e. stages according to FIGO, primary cytoreduction extent, tumour histologic subtype and grade, as well as year of diagnosis and treatment. RESULTS: The 5-year overall survival rate was 42.9% for BRCA1-OC patients and 34.3% for SOC patients (p = 0.354). Mean time to progression was 22.7 and 14.5 months for BRCA1-OC and SOC group, respectively (p = 0.05). Complete response to pri-mary surgery and first line chemotherapy was obtained in 42.5% and 37.9% of cases, respectively; the difference, however, did not reach the statistical significance. CONCLUSIONS: Results of combined treatment in the group of BRCA1-related OC patients seem to be better than in the group of sporadic ovarian cancer patients.

A phase 1, open-label, drug-drug interaction study of rucaparib with rosuvastatin and oral contraceptives in patients with advanced solid tumors.

PURPOSE: This study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives. METHODS: Patients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis. RESULTS: Thirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug-drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration-time curve from time zero to last quantifiable measurement (AUC0-last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment. CONCLUSION: Rucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib. ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.

Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer.

The aim of the study was to analyze the frequency and magnitude of association of 21 recurrent founder germline mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 genes with ovarian cancer risk among unselected patients in Poland. We genotyped 21 recurrent germline mutations in BRCA1 (9 mutations), BRCA2 (4 mutations), RAD51C (3 mutations), PALB2 (2 mutations), and CHEK2 (3 mutations) among 2270 Polish ovarian cancer patients and 1743 healthy controls, and assessed the odds ratios (OR) for developing ovarian cancer for each gene. Mutations were detected in 369 out of 2095 (17.6%) unselected ovarian cancer cases and 117 out of 1743 (6.7%) unaffected controls. The ovarian cancer risk was associated with mutations in BRCA1 (OR = 40.79, 95% CI: 18.67-114.78; p = 0.29 × 10-15), in BRCA2 (OR = 25.98; 95% CI: 1.55-434.8; p = 0.001), in RAD51C (OR = 6.28; 95% CI 1.77-39.9; p = 0.02), and in PALB2 (OR 3.34; 95% CI: 1.06-14.68; p = 0.06). There was no association found for CHEK2. We found that pathogenic mutations in BRCA1, BRCA2, RAD51C or PALB2 are responsible for 12.5% of unselected cases of ovarian cancer. We recommend that all women with ovarian cancer in Poland and first-degree female relatives should be tested for this panel of 18 mutations.

[Chemotherapy of advanced non small cell lung cancer: effect on survival and symptoms affecting quality of life]. / Ocena wplywu chemioterapii na czas przezycia i wybrane objawywplywajace na jakosc zycia chorych na niedrobnokomórkowegoraka pluca w IIIB i IV stopniu zaawansowania.

INTRODUCTION: The study presents treatment results of 168 patients with non small cell lung cancer in stage IIIB and IV treated since year 2002 to 2006 in Oncological Center in Cracow. MATERIAL AND METHODS: Four regimens of chemotherapy: EP (cisplatin, vepesid), MVP (mitomycin C, vinblastin, cisplatin), PN (cisplatin,vinorelbin) and PG (cisplatin, gemcytabin) were used. RESULTS: Average survival time in group treated with MVP regimen was 7,8 months (median 4,3 months), PG 7,1 months (median 7,3 months), EP 10,2 months (median 7,5 months), PN 14,1 months (median 9,8 months). Differences in median survival time were not significant. Average time to progression in group treated with MVP regimen was 3,5 months (median 2,6 months), PG 5,2 months (median 5,8 months): EP 6,6 months (median 5,2 months), PN 6,7 months (median 5,6 months). Improvement in control of symptoms regarding dyspnea, pain and cough was reached in 60%, 38,7% and 60% of patients respectively. There were no significant differences between chemotherapy regimens regarding improvement in symptoms control. CONCLUSIONS: Cisplatin + vinorelbin regimen can be recommended as standard method because of the best treatment results.

Analysis of adverse events of sunitinib in patients treated for advanced renal cell carcinoma.

INTRODUCTION: Treatment of the metastatic stage of renal cell carcinoma is specific because classical chemotherapy is not applicable here. The treatment is mainly based on molecularly targeted drugs, including inhibitors of tyrosine kinases. In many cases the therapy takes many months, and patients often report to general practitioners due to adverse events. In this article, the effectiveness and side effects of one of these drugs are presented. The aim of the study was to analyse of the toxicity and safety of treatment with sunitinib malate in patients with clear cell renal cell carcinoma in the metastatic stage. MATERIAL AND METHODS: Adverse events were analyzed using retrospective analysis of data collected in a group of 39 patients treated in the Department of Systemic and Generalized Malignancies in the Cancer Center in Krakow, Poland. RESULTS: Toxicity of treatment affected 50% of patients. The most common side effects observed were hypertension, thrombocytopenia, stomatitis, diarrhea and weakness. Grade 3 serious adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version 4 affected up to 10% of patients. The most common serious adverse events were hypertension and fatigue. CONCLUSIONS: Sunitinib malate is characterized by a particular type of toxicity. Knowledge of the types and range of adverse events of this drug is an important part of oncological and internal medicine care.

Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study.

PURPOSE: To compare overall survival (OS) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer. PATIENTS AND METHODS: The Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was a phase II, randomized, open-label, multicenter trial. Postmenopausal women with estrogen receptor-positive, locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or anastrozole 1 mg (daily). The primary end point (clinical benefit rate [72.5% and 67.0%]) and a follow-up analysis (median time to progression [23.4 months and 13.1 months]) have been reported previously for fulvestrant 500 mg and anastrozole, respectively. Subsequently, the protocol was amended to assess OS by unadjusted log-rank test after approximately 65% of patients had died. Treatment effect on OS across several subgroups was examined. Tolerability was evaluated by adverse event monitoring. RESULTS: In total, 205 patients were randomly assigned (fulvestrant 500 mg, n = 102; anastrozole, n = 103). At data cutoff, 61.8% (fulvestrant 500 mg, n = 63) and 71.8% (anastrozole, n = 74) had died. The hazard ratio (95% CI) for OS with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98; P = .04; median OS, 54.1 months v 48.4 months). Treatment effects seemed generally consistent across the subgroups analyzed. No new safety issues were observed. CONCLUSION: There are several limitations of this OS analysis, including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed, and that not all patients participated in additional OS follow-up. However, the present results suggest fulvestrant 500 mg extends OS versus anastrozole. This finding now awaits prospective confirmation in the larger phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer) trial (ClinicalTrials.gov identifier: NCT01602380).