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Comparative Proteomic Analysis of Advanced Ovarian Cancer Tissue to Identify Potential Biomarkers of Responders and Nonresponders to First-Line Chemotherapy of Carboplatin and Paclitaxel.

ABSTRACT: Conventional treatment for advanced ovarian cancer is an initial debulking surgery followed by chemotherapy combination of carboplatin and paclitaxel. Despite initial high response, three-fourths of these women experience disease recurrence with a dismal prognosis. Patients with advanced-stage ovarian cancer who underwent cytoreductive surgery were enrolled and tissue samples were collected. Post surgery, these patients were started on chemotherapy and followed up till the end of the cycle. Fluorescence-based differential in-gel expression coupled with mass spectrometric analysis was used for discovery phase of experiments, and real-time polymerase chain reaction, Western blotting, and pathway analysis were performed for expression and functional validation of differentially expressed proteins. While aldehyde reductase, hnRNP, cyclophilin A, heat shock protein-27, and actin are upregulated in responders, prohibitin, enoyl-coA hydratase, peroxiredoxin, and fibrin-? are upregulated in the nonresponders. The expressions of some of these proteins correlated with increased apoptotic activity in responders and decreased apoptotic activity in nonresponders. Therefore, the proteins qualify as potential biomarkers to predict chemotherapy response.

SUBMITTER: Sehrawat U

PROVIDER: S-EPMC4795487 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Comparative Proteomic Analysis of Advanced Ovarian Cancer Tissue to Identify Potential Biomarkers of Responders and Nonresponders to First-Line Chemotherapy of Carboplatin and Paclitaxel.

Sehrawat Urmila U Pokhriyal Ruchika R Gupta Ashish Kumar AK Hariprasad Roopa R Khan Mohd Imran MI Gupta Divya D Naru Jasmine J Singh Sundararajan Baskar SB Mohanty Ashok Kumar AK Vanamail Perumal P Kumar Lalit L Kumar Sunesh S Hariprasad Gururao G

Biomarkers in cancer 20160316

Conventional treatment for advanced ovarian cancer is an initial debulking surgery followed by chemotherapy combination of carboplatin and paclitaxel. Despite initial high response, three-fourths of these women experience disease recurrence with a dismal prognosis. Patients with advanced-stage ovarian cancer who underwent cytoreductive surgery were enrolled and tissue samples were collected. Post surgery, these patients were started on chemotherapy and followed up till the end of the cycle. Fluo ...[more]

PMID: 26997873

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Project description:The use of weekly chemotherapy for the treatment of patients with advanced-stage serous-type epithelial Tubo-ovarian cancer (ETOC), and primary peritoneal serous carcinoma (PPSC) is acceptable as the front-line postoperative chemotherapy after primary cytoreductive surgery (PCS). The main component of dose-dense chemotherapy is weekly paclitaxel (80 mg/m2), but it would be interesting to know what is the difference between combination of triweekly cisplatin (20 mg/m2) or triweekly carboplatin (carboplatin area under the curve 5-7 mg/mL per min [AUC 5-7]) in the dose-dense paclitaxel regimen. Therefore, we compared the outcomes of women with Gynecology and Obstetrics (FIGO) stage IIIC ETOC and PPSC treated with PCS and a subsequent combination of dose-dense weekly paclitaxel and triweekly cisplatin (paclitaxel-cisplatin) or triweekly carboplatin using AUC 5 (paclitaxel-carboplatin). Between January 2010 and December 2016, 40 women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC EOC, FTC, or PPSC were enrolled, including 18 treated with paclitaxel-cisplatin and the remaining 22 treated with paclitaxel-carboplatin. There were no statistically significant differences in disease characteristics of patients between two groups. Outcomes in paclitaxel-cisplatin group seemed to be little better than those in paclitaxel-carboplatin (median progression-free survival [PFS] 30 versus 25 months as well as median overall survival [OS] 58.5 versus 55.0 months); however, neither reached a statistically significant difference. In terms of adverse events (AEs), patients in paclitaxel-carboplatin group had more AEs, with a higher risk of neutropenia and grade 3/4 neutropenia, and the need for a longer period to complete the front-line chemotherapy, and the latter was associated with worse outcome for patients. We found that a period between the first-time chemotherapy to the last dose (6 cycles) of chemotherapy >21 weeks was associated with a worse prognosis in patients compared to that ?21 weeks, with hazard ratio (HR) of 81.24 for PFS and 9.57 for OS. As predicted, suboptimal debulking surgery (>1 cm) also contributed to a worse outcome than optimal debulking surgery (?1 cm) with HR of 14.38 for PFS and 11.83 for OS. Based on the aforementioned findings, both regimens were feasible and effective, but maximal efforts should be made to achieve optimal debulking surgery and following the on-schedule administration of dose-dense weekly paclitaxel plus triweekly platinum compounds. Randomized trials validating the findings are warranted.

Project description:Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3?+?3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or???1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n?=?5) or palliative (n?=?10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n?=?4), thrombocytopenia (n?=?3) and increased GGT (n?=?3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (?22%, p?=?0.013) and decreased the Pt clearance (?-28%, p?=?0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.

Project description:The interval required for haematological reconstitution following myelosuppressive chemotherapy can be reduced by the infusion of autologous peripheral blood progenitor cells (PBPCs). When carboplatin (C) and paclitaxel (P) are followed by granulocyte colony-stimulating factor (GCSF), multiple courses can be given at 10-day intervals with the autologous PBPCs from a unit of whole blood with each cycle. We extended this approach and defined the dose-limiting toxicity and maximum-tolerated dose for the addition of gemcitabine (G) to CP for patients (pts) with EOC in a phase I-II study of increasing doses of G (0, 800, 1000 and 1250 mg x m(-2)) over four cohorts with C at area under curve (AUC) 6, plus P at 175 mg x m(-2) 3 h(-1) every 10 days for six cycles. Granulocyte colony-stimulating factor 5 microg x kg(-1) day(-1) was given s.c. days 1-10 and 450 ml whole blood was venesected before each treatment, stored untreated at 4 degrees C and reinfused 24 h later. In all, 17 patients with EOC either bulky stage IV or recurrent after treatment-free interval >12 months were treated over 30 months. Of the 17 patients, 13 completed six cycles (one patient stopped early with PD, three with toxicity), interdose interval 9-28 (median 10) days. Delays occurred in four patients due to infection or malaise, and there were no dose reductions. Haematological toxicity was not considered to be dose limiting. Febrile neutropenia was uncommon (2 patients), but grade III/IV thrombocytopenia was seen across all cohorts. Treatment was not delayed for thrombocytopenia and no bleeding complications occurred. Grade III transaminitis was seen in all patients in cohort 4 and grade IV toxicity, considered to be dose limiting, occurred in one. Responses were observed at all dose levels with six CR, seven PR, three SD and one PD. Dose intense GCP was deliverable over six cycles with manageable haematological toxicity, but with dose-limiting hepatic toxicity in cohort 4. The MTD was gemcitabine 1000 mg x m(-2), carboplatin AUC 6, paclitaxel 175 mg x m(-2) given every 10 days for six cycles.

Dataset Information

Comparative Proteomic Analysis of Advanced Ovarian Cancer Tissue to Identify Potential Biomarkers of Responders and Nonresponders to First-Line Chemotherapy of Carboplatin and Paclitaxel.

Publications

Comparative Proteomic Analysis of Advanced Ovarian Cancer Tissue to Identify Potential Biomarkers of Responders and Nonresponders to First-Line Chemotherapy of Carboplatin and Paclitaxel.

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