ObjectiveThe purpose of this study was to determine the prognostic implications of the pretreatment neutrophil-to-lymphocyte ratio (NLR) and its dynamic change during chemotherapy in patients with advanced epithelial ovarian cancer undergoing neoadjuvant chemotherapy.MethodsWe performed a retrospective analysis of 203 patients who underwent neoadjuvant chemotherapy prior to interval debulking surgery for advanced-stage ovarian cancer at Yonsei Cancer Hospital between 2007 and 2015. Pretreatment NLR was evaluated before starting neoadjuvant chemotherapy. Change in NLR was defined as the post-neoadjuvant NLR value divided by the initial value. The correlation of NLR and its dynamic change with chemotherapy response score, response rate, and recurrence was analyzed.ResultsThe NLR ranged from 0.64 to 22.8. In univariate analyses, a higher pretreatment NLR (>3.81) was associated with poor overall survival (OS), but not progression-free survival (PFS). Through multivariate analysis, high pretreatment NLR was shown to be an independent parameter affecting OS, but not necessarily PFS. Changes in NLR during chemotherapy were better predictors of PFS than baseline NLR. Patients with increased NLR during chemotherapy showed significantly poor PFS, and this change was an independent predictor of PFS.ConclusionPretreatment NLR and its dynamic change during chemotherapy may be important prognostic factors in patients who undergo neoadjuvant chemotherapy.

BackgroundThere is currently no consensus regarding the optimal number of chemotherapy cycles to be administered before and after interval debulking surgery (IDS) in patients with advanced ovarian cancer. This study aimed to evaluate the impact of the number of neoadjuvant chemotherapy (NAC) and postoperative adjuvant chemotherapy (POAC) cycles on the survival of patients with advanced ovarian cancer undergoing NAC/IDS/POAC.MethodsWe retrospectively reviewed data from 203 patients who underwent NAC/IDS/POAC at Yonsei Cancer Hospital between 2006 and 2016. All patients underwent taxane plus carboplatin chemotherapy for NAC and POAC. The patient outcomes were analyzed according to the number of NAC, POAC, and total chemotherapy (NAC+POAC) cycles.ResultsPatients who received fewer than 6 cycles of total chemotherapy (n = 8) had poorer progression-free survival (PFS) and overall survival (OS) than those completing at least 6 cycles (p = 0.005 and p<0.001, respectively). Among patients who completed at least 6 cycles of total chemotherapy (n = 189), Kaplan-Meier analysis revealed no significant difference in either PFS or OS according to the number of NAC cycles (1–3 vs. ≥4; p = 0.136 and p = 0.267, respectively). Among patients who experienced complete remission after 3 cycles of POAC (n = 98), the addition of further POAC cycles did not improve the PFS or OS (3 vs. ≥4; p = 0.641 and p = 0.104, respectively).ConclusionIDS after 4 cycles of NAC may be a safe and effective option when completing 6 cycles of total chemotherapy. Furthermore, the addition of more than 3 cycles of POAC does not appear to influence the survival of patients achieving completion remission after 3 cycles of POAC.

Purpose: Frameshift mutations in coding mononucleotide repeats (cMNR) are common in tumors with high microsatellite instability (MSI-H). These mutations generate mRNAs containing abnormal coding sequences and premature termination codons (PTC). Normally, mRNAs containing PTCs are degraded by nonsense-mediated mRNA decay (NMD). However, mRNAs containing PTCs located in the last exon are not subject to degradation by NMD (NMD-irrelevant). This study aimed to discover whether genes with frameshift mutations in the last exon generate truncated mutant proteins.Experimental Design: We identified 66 genes containing cMNRs in the last exon by bioinformatic analysis. We found frequent insertion/deletion mutations in the cMNRs of 29 genes in 10 MSI-H cancer cell lines and in the cMNRs of 3 genes in 19 MSI-H cancer tissues. We selected 7 genes (TTK, TCF7L2, MARCKS, ASTE1, INO80E, CYHR1, and EBPL) for mutant mRNA expression analysis and 3 genes (TTK, TCF7L2, and MARCKS) for mutant protein expression analysis.Results: The PTC-containing NMD-irrelevant mRNAs from mutated genes were not degraded. However, only faint amounts of endogenous mutant TTK and TCF7L2 were detected, and we failed to detect endogenous mutant MARCKS. By polysome analysis, we showed that mRNAs from genomic mutant MARCKS constructs are normally translated. After inhibiting 3 protein degradation pathways, we found that only inhibition of the proteasomal pathway facilitated the rescue of endogenous mutant TTK, TCF7L2, and MARCKS.Conclusions: Our findings indicate that cancer cells scavenge potentially harmful neopeptide-containing mutant proteins derived from NMD-irrelevant abnormal mRNAs via the ubiquitin-proteasome system, and these mutant proteins may be important substrates for tumor-specific antigens.

Various kinetic parameters of serum CA-125 have been reported to have better correlation with outcomes for patients treated with neoadjuvant chemotherapy (NAC). This study aimed to compare the available kinetic parameters of serum CA-125 in an external cohort of advanced-stage ovarian cancer. Using the cancer registry databases from the Yonsei Cancer Hospital, we retrospectively reviewed 210 patients with advanced-stage ovarian cancer, treated with NAC followed by interval debulking surgery. We compared area under the receiver-operating characteristics curves (AUCs), false negative rate, and negative predictive value (NPV) using 10 different models for optimal cytoreduction and platinum resistance. In addition, we compared incremental AUC for progression-free survival (PFS) and overall survival (OS). No gross residual tumor was observed in 37.0% and residual tumors <1 cm in 82.2% of patients. No model using CA-125 kinetic parameters had an AUC higher than >0.6 for predicting optimal cytoreduction. After adjusting for age, BMI, disease stage, and histologic subtypes, all models had an AUC >0.70 for predicting platinum resistance. However, no model had a high enough NPV (highest value = 82.0%) to avoid chemotherapy futility. For survival outcomes, no model had an incremental AUC >0.70 for predicting either PFS or OS. None of the proposed serum CA-125 kinetic parameters showed high accuracy in predicting optimal cytoreduction, platinum resistance, or survival in patients receiving NAC. For advanced-stage ovarian cancer treated with NAC, there is a need to discover reliable biomarkers to better stratify patient response groups for optimal treatment decision-making.