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Influence of CYP3A4 genotypes in the outcome of serous ovarian cancer patients treated with first-line chemotherapy: implication of a CYP3A4 activity profile.

ABSTRACT: CYP3A4 is a key enzyme involved in the metabolism of numerous compounds, such as paclitaxel, and its activity shows an extensive inter-individual variation which can influence treatment response. The study's purpose was to investigate the potential predictive role of a CYP3A4 profile (CYP3A4*1B, rs2740574 and CYP3A4*22, rs35599367) in serous ovarian cancer patients treated with first-line chemotherapy (paclitaxel and cisplatin or carboplatin), after cytoreductive surgery. CYP3A4*1B and CYP3A4*22 genotypes were determined by Nested PCR-RFLP and Taqman® Allelic Discrimination, respectively. We observed that the mean survival rates were statistically different according the patients CYP3A4 genotypes. The group of patients carrying the CYP3A4*1B G allele present a decreased mean survival rate when compared with AA genotype patients (103.93 and 134.44 months, respectively, p = 0.010). This result is consistent after multivariate Cox regression analysis (HR, 2.15; 95% CI, 1.03-4.52; p = 0.043). The combination of CYP3A4*1B and CYP3A4*22 polymorphisms result in the definition of a CYP3A4 activity profile: the group of patients with a higher CYP3A4 activity profile had significantly diminished survival when compared with patients with a lower CYP3A4 activity profile (101.06 and 134.44 months, respectively, p = 0.012). Multivariate Cox regression analysis revealed a diminished overall survival time for patients with CYP3A4 high activity profile (HR, 2.29; 95% CI, 1.05-5.02; p = 0.038). The definition of a CYP3A4 activity profile resulted in the increase of prediction ability, using Harrels's concordance indexes (C-index from 0.617 to 0.626). To conclude, our results demonstrate an association between CYP3A4*1B and a diminished overall survival of patients with serous ovarian cancer. The definition of a CYP3A4 activity profile proved to be benefic and the CYP3A4 high activity profile was associated with a lower overall survival. We consider that the definition of a CYP3A4 activity profile might be useful as molecular marker for predicting the clinical outcome of serous ovarian cancer patients.

SUBMITTER: Assis J

PROVIDER: S-EPMC3731187 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Influence of CYP3A4 genotypes in the outcome of serous ovarian cancer patients treated with first-line chemotherapy: implication of a CYP3A4 activity profile.

Assis Joana J Pereira Deolinda D Gomes Mónica M Marques Dânia D Marques Inês I Nogueira Augusto A Catarino Raquel R Medeiros Rui R

International journal of clinical and experimental medicine 20130801 7

CYP3A4 is a key enzyme involved in the metabolism of numerous compounds, such as paclitaxel, and its activity shows an extensive inter-individual variation which can influence treatment response. The study's purpose was to investigate the potential predictive role of a CYP3A4 profile (CYP3A4*1B, rs2740574 and CYP3A4*22, rs35599367) in serous ovarian cancer patients treated with first-line chemotherapy (paclitaxel and cisplatin or carboplatin), after cytoreductive surgery. CYP3A4*1B and CYP3A4*22 ...[more]

PMID: 23936594

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Project description:Purpose of reviewEpithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future.Recent findingsRecent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemotherapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line multi-modality therapy. Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and plasma biomarkers to exploit the potential of these highly efficacious targeted agents.

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:ObjectiveUterine serous carcinoma (USC) is a rare highly aggressive disease. In the present study, we aimed to investigate the survival implication of the systematic lymphadenectomy in patients who underwent surgery for apparent early-stage USC.MethodsConsecutive patients with apparent early-stage USC surgically treated at six Italian referral cancer centers were analyzed. A comparison was made between patients who underwent retroperitoneal staging including at least pelvic lymphadenectomy "LND" vs. those who underwent hysterectomy alone "NO-LND". Baseline, surgical and oncological outcomes were analyzed. Kaplan- Meier curves were calculated for disease-free survival (DFS) and disease-specific survival (DSS). Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR).ResultsOne hundred forty patients were analyzed, 106 LND and 34 NO-LND. NO-LND group (compared to LND group) included older patients (median age, 73 vs.67 years) and with higher comorbidities (median Charlson Comorbidity Index, 6 vs. 5) (p<0.001). No differences in terms of recurrence rate (LND vs. NO-LND, 33.1% vs. 41.4%; p=0.240) were observed. At Cox regression analysis lymphadenectomy did not significantly influence DFS (HR=0.59; 95% confidence interval [CI]=0.32-1.08; p=0.09), and DSS (HR=0.14; 95% CI=0.02-1.21; multivariable analysis p=0.07). Positive node was independently associated with worse DFS (HR=6.22; 95% CI=3.08-12.60; p<0.001) and DSS (HR=5.51; 95% CI=2.31-13.10; p<0.001), while adjuvant chemotherapy was associated with improved DFS (HR=0.38; 95% CI=0.17-0.86; p=0.02) and age was independently associated with worse DSS (HR=1.07; 95% CI=1.02-1.13; p<0.001).ConclusionsAlthough lymphadenectomy did not show survival benefits in patients who underwent surgery for apparent early-stage USC, the presence of lymph node metastasis was the main adverse prognostic factors, supporting the prognostic role of the retroperitoneal staging also in this histological subtype.

Project description:BackgroundChemotherapy resistance remains a major obstacle in the treatment of women with ovarian cancer. Establishing predictive markers of chemoresponse would help to individualize therapy and improve survival of ovarian cancer patients. Chemotherapy resistance in ovarian cancer has been studied thoroughly and several non-overlapping single genes, gene profiles and copy number alterations have been suggested as potential markers. The objective of this study was to explore genetic alterations behind chemotherapy resistance in ovarian cancer with the ultimate aim to find potential predictive markers.MethodsTo create the best opportunities for identifying genetic alterations of importance for resistance, we selected a homogenous tumor material concerning histology, stage and chemotherapy. Using high-resolution whole genome array comparative genomic hybridization (CGH), we analyzed the tumor genomes of 40 fresh-frozen stage III ovarian serous carcinomas, all uniformly treated with combination therapy paclitaxel/carboplatin. Fisher's exact test was used to identify significant differences. Subsequently, we examined four genes in the significant regions (EVI1, MDS1, SH3GL2, SH3KBP1) plus the ABCB1 gene with quantitative real-time polymerase chain reaction (QPCR) to evaluate the impact of DNA alterations on the transcriptional level.ResultsWe identified gain in 3q26.2, and losses in 6q11.2-12, 9p22.3, 9p22.2-22.1, 9p22.1-21.3, Xp22.2-22.12, Xp22.11-11.3, and Xp11.23-11.1 to be significantly associated with chemotherapy resistance. In the gene expression analysis, EVI1 expression differed between samples with gain versus without gain, exhibiting higher expression in the gain group.ConclusionIn conclusion, we detected specific genetic alterations associated with resistance, of which some might be potential predictive markers of chemotherapy resistance in advanced ovarian serous carcinomas. Thus, further studies are required to validate these findings in an independent ovarian tumor series.

Dataset Information

Influence of CYP3A4 genotypes in the outcome of serous ovarian cancer patients treated with first-line chemotherapy: implication of a CYP3A4 activity profile.

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Influence of CYP3A4 genotypes in the outcome of serous ovarian cancer patients treated with first-line chemotherapy: implication of a CYP3A4 activity profile.

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