Clinical features and outcomes of germline mutation BRCA1-linked versus sporadic ovarian cancer patients.

BACKGROUND: The role of germline mutations in BRCA1 and BRCA2 genes in the risk of the development of ovarian cancer is clinically well established. BRCA1/2 testing seems to have increasing role in clinical management in patients with advanced ovarian cancer who require treatment with poly(ADP-ribose) polymerase inhibitors. METHODS: Between 2002 - 2008, 125 consecutive patients with ovarian cancer were categorized as having three founder mutations in the BRCA1 gene in Poland as: 5382insC [exon 20], 4153delA [exon 11.17], and 300 T > G [exon 5]. PFS (progression free survival) and OS (overall survival) were determined by Kaplan-Meier analysis with log rank test, univariate comparisons, and multivariate regression analysis using Cox proportional hazards model. RESULTS: Of the 125 patients, the founder mutations of BRCA1 were reported in 17 patients (13.6 %). The median OS was longer for BRCA mutated patients (not reached vs 35.6 months, p = 0.041). PFS was similar for both kinds of ovarian cancer. In multivariate analysis, age ≥70 years, suboptimal surgery, and BRCA1 wild type were poor prognostic factors. The BRCA1 mutation reduced the likelihood of death in ovarian cancer by 86 % (HR 0.14; CI: 0.032-0.650, p = 0.012). CONCLUSION: In conclusion, we found better overall survival for ovarian cancer patients with BRCA1 germline mutations in comparison with patients without these mutations (sporadic) ovarian cancer. Thus, BRCA1 germline mutations appear to be an independent prognostic factor for ovarian 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.

Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: a randomised phase II study.

BACKGROUND: The aim of this study was to examine the effect of magnesium supplementation on nephrotoxicity accompanying standard cisplatin-based chemotherapy in patients with epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A double-blind, placebo-controlled, randomised study was conducted in which study arm magnesium sulphate (5 g) was administered before each course of standard chemotherapy with paclitaxel (135 mg/m(2)/24 h) plus cisplatin (75 mg/m(2)) every 3 weeks in patients with EOC. Magnesium subcarbonate (500 mg), three times per day orally, was administered during the treatment intervals. The control arm was administered a placebo instead of both magnesium salts. Magnesium serum levels (sMg) and GFR markers: serum levels of creatinine (sCr), Cockroft-Gault (ClCG) and Modification Diet of Renal Disease (MDRD) formulae were recorded before each cycle, and 3 weeks after the sixth course. RESULTS: 41 EOC patients were randomised and 40 were eligible. sMg varied significantly between the supplemented and placebo groups (p<0.0001). The control group showed a significantly greater decrease of GFR assessed by: sCr (p=0.0069), ClCG (p=0.0077) and MDRD (p=0.032) formulae compared with the magnesium supplemented group. CONCLUSIONS: These results demonstrate the nephroprotective effect of magnesium supplementation during chemotherapy with cisplatin.

Control of aggressive fibromatosis by treatment with imatinib mesylate. A case report and review of the literature.

OBJECTIVE: There has been only one report available that focuses on the treatment with imatinib mesylate of two individual persons with aggressive fibromatosis. The authors concluded that after long-term treatment, for 9 and 11 months, with imatinib mesylate, both patients demonstrated radiographic and clinical responses. The novel therapy should be considered as salvage in patients with aggressive fibromatosis expressed platelet-derived growth factor receptor-alfa, beta (PDGFR-alfa, PDGFR-beta), and/or c-kit, whose tumors are uncontrollable by the standard management. On the other hand, the number of kinases blocked by imatinib mesylate is notching up, for instance the tyrosine kinase, which is associated with macrophage-colony stimulating factor receptor (M-CSFR). METHODS: The patient was suffering from aggressive fibromatosis after prior therapy including surgery (R2), radiotherapy, and systemic treatment with combination of tamoxifen and sulindac. The tumor specimen was immunostained for PDGFR-beta and c-kit (CD117), and PDGFR-alfa and cytokines platelet-derived growth factor-alfa and beta were not assessed. The tests for both assessed molecules revealed negative results. In spite of this, the patient underwent a unique treatment with imatinib mesylate at the dose of 400 mg orally once daily for 3 years and 2 months. RESULTS: After three months of the therapy, radiographic (met criteria of SD but small decrease of the tumor was noted) and clinical responses were recorded for the first time. The same was seen after 6 and 13 months of therapy continuation with imatinib mesylate. Currently, the patient is treated with imatinib mesylate (400 mg orally once daily) without any toxicity effects. The last MRI revealed readily a smaller tumor (35 x 20 mm) after such a therapy lasted more than 3 years. CONCLUSIONS: Treatment with imatinib mesylate has been a well-accepted therapy for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). There have been established four kinases (p210(bcr/abl), c-kit, PDGFR-alfa, PDGFR-beta) suggested as the target for imatinib mesylate. Other potential targets will be discovered as it has lately been determined that M-CSFR kinase activity was blocked by imatinib mesylate. The salvage therapy for aggressive fibromatosis with imatinib mesylate seems to be an attractive opportunity for patients with the advanced disease, whose prior therapy failed.