Efficacy Of Platinum-based Chemotherapy Research Articles

DNA damage response and repair (DDR) mutations predict the efficacy of platinum-based chemotherapy for advanced non-small cell lung cancer: A retrospective cohort study.

e21635 Background: DNA damage response and repair (DDR) pathway alteration is known as a predictive biomarker of platinum-based chemotherapy sensitivity in urothelial carcinoma, breast cancer, ovarian cancer, and prostate cancer. However, the predictive value of DDR in patients with non-small cell lung cancer (NSCLC) is still uncertain. This study investigated the DDR mutations (MUT) of NSCLC to identify potential predictive biomarker. Methods: A retrospective analysis of patients with NSCLC was performed. Targeted exon sequencing with the Next Generation Sequencing (NGS) were performed for 298 patients, and they were divided into two groups based on the presence or absence of mutations in 36 DDR genes. Results: 50 patients treated with platinum-based chemotherapy were identified, of which 17 harbored alterations in DDR genes. The median age was 60.5 years (range, 43 to 79 years). A total of 50 patients were evaluated, the objective response rate (ORR) of patients with DDR MUT was 17.6%, ORR 0% for DDR wild-type (WT), and the disease control rate (DCR) was 76.4% for DDR MUT, 48.5% for DDR WT. In terms of survival analysis, patients with DDR MUT had significantly improved median progression-free survival (mPFS) of 9.2 months compared with 4.8 months for DDR WT (Hazard Ratio (HR) = 0.4134, log-rank P = 0.0117). When EGFR and ALK mutations were excluded, there was no significant difference in mPFS between DDR MUT and WT, but DDR MUT has a tendency to be higher than WT (mPFS: 8.0 vs. 4.7 months, HR = 0.5060, log-rank P = 0.1022). Nevertheless, there was no significant difference in the median overall survival (mOS) between two groups (DDR MUT vs. DDR WT: 21.7 vs. 29.4 months, HR = 1.537, log-rank P = 0.3756), even after EGFR and ALK mutations were excluded, no significant difference can also be gained (HR = 1.818, log-rank P = 0.3972). Conclusions: DDR mutations may be a positive predictive biomarker for response to platinum-based chemotherapy in patients with NSCLC.

Platinum-Based Chemotherapy in Metastatic Prostate Cancer With DNA Repair Gene Alterations.

Alterations in DNA damage repair (DDR) genes occur in up to 25% of patients with metastatic castration-resistant prostate cancer (mCRPC) and may sensitize to platinum chemotherapy. We aimed to evaluate the efficacy of platinum-based chemotherapy in DDR-mutant (DDRmut) mCRPC. We assessed response to platinum chemotherapy based on DDR gene alteration status in men with mCRPC who underwent tumor and germline genomic profiling. Patients with deleterious alterations in a gene panel that included BRCA2, BRCA1, ATM, PALB2, FANCA, and CDK12 were considered DDRmut. A total of 109 patients with mCRPC received platinum-based chemotherapy between October 2013 and July 2018. Sixty-four of 109 patients were taxane refractory and poly (ADP-ribose) polymerase inhibitor (PARPi) naïve. Within this subset, DDRmut was found in 16/64 patients (25%) and was associated with an increased likelihood of achieving a prostate-specific antigen (PSA) decline of 50% or more from baseline (PSA50; odds ratio, 7.0; 95% CI, 1.9 to 29.2). Time on platinum chemotherapy tended to be longer in the DDRmut group (median, 3.0 v 1.6 months; hazard ratio, 0.55, 95% CI, 0.29 to 1.24). No difference in survival was detected. Of 8 patients with DDRmut disease who received platinum-based therapy after a PARPi, 3/7 evaluable patients had radiographic partial response or stable disease, and 2/7 had a PSA50 response. None of 4 patients with ATM mutations had platinum responses regardless of prior PARPi exposure. Patients with DDRmut disease had better response to platinum-based chemotherapy, suggesting that DDR status warrants prospective validation as a potential biomarker for patient selection. Responses to platinum chemotherapy were observed in BRCA-altered prostate cancer after PARPi progression. Additional studies are needed to determine the predictive role of individual genes on platinum sensitivity in the context of other clinical and genomic factors.

Correlation between miR-138-5p expression and efficacy of platinum-based chemotherapy in advanced gastric cancer patients.

BackgroundWe investigated the relationship between levels of microRNA (miR)-138-5p in plasma and tumor tissues from advanced gastric cancer patients, and the efficacy of first-line platinum-based chemotherapy.MethodsMiR-138-5p expression was measured by qRT-PCR in cancerous tissues and plasma from 51 advanced gastric cancer patients, in paracancerous tissues and in plasma from healthy volunteers as control. All patients received first-line platinum-based chemotherapy. Correlations between miR-138-5p expression and the treatment efficacy, progression-free survival (PFS), and overall survival (OS) of first-line chemotherapy were evaluated.ResultsSignificantly lower levels of miR-138-5p were detected in gastric cancer tissues compared with paracancerous tissues and in the plasma of patients compared with control subjects (both P<0.05). A positive correlation was detected between the treatment efficacy and miR-138-5p expression in both cancer tissues and plasma (P<0.05). Receiver-operating characteristic (ROC) curves were constructed to determine the optimal miR-138-5p cutoff value for predicting the efficacy of platinum-based chemotherapy. Patients with high miR-138-5p expression in either tissues (≥0.081) or plasma (≥0.047) had better treatment responses and longer PFS and OS than patients with low miR-138-5p expression (P<0.05), and multivariate analyses confirmed miR-138-5p expression as a promising prognostic biomarkers.ConclusionsOur study suggested that miR-138-5p expression in cancer tissues or plasma could be a useful predictive biomarker for the efficacy of platinum-based chemotherapy and prognoses in advanced gastric cancer patients.

Effects of microRNA-1271 on ovarian cancer via inhibition of epithelial-mesenchymal transition and cisplatin resistance.

Efficacy of platinum based-chemotherapy is limited by cisplatin (DDP) resistance, however, the underlying mechanism of cisplatin resistance remains unclear. We aimed to investigate the role of miR-1271 in cisplatin-resistant ovarian cancer cells. Transfection of miR-1271 mimic and inhibitor was performed to study the role of miR-1271 in ovarian cancer. Cell viability was assessed by Cell Counting Kit (CCK)-8 assay. Flow cytometry was used to determine the apoptosis rates. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect mRNA and protein expressions. Target predicted by Targetscan7.2 was confirmed by dual-luciferase activity assay. Mammalian target of rapamycin (mTOR) siRNA (simTOR) co-transfection was performed to verify the role of mTOR in the suppression effect of miR-1271 on ovarian cancer. In SKOV3 cells, miR-1271 overexpression significantly decreased cell viability and up-regulated apoptosis rate (from 5.54% of control to 24.03%). MiR-1271 adversely affected SKOV3 cell migration and invasion, and induced the upregulation of E-cadherin and downregulation of N-cadherin and alpha-smooth muscle actin (α-SMA). Moreover, SKOV3/DDP cells had a lower miR-1271 level, and enhancing miR-1271 contributed strongly to cisplatin-induced apoptosis through altering the expressions of B-cell lymphoma-2 associated X protein (BAX), cleaved caspase-3 and B-cell lymphoma 2 (Bcl-2). In contrast, the opposite result was observed in miR-1271 inhibitor. mTOR was identified to be a target of miR-1271. SimTOR partially reversed the increased cell viability under the effect of miR-1271 inhibitor. Our data indicate that miR-1271 can inhibit the ovarian cancer epithelial-mesenchymal transition (EMT) and sensitize resistant cells to cisplatin-induced apoptosis through blocking mTOR expression.

Efficacy of Platinum-based Chemotherapy in Platinum-resistant Ovarian Cancer) (EPITOC)

Efficacy of Platinum-based Chemotherapy in Platinum-resistant Ovarian Cancer) (EPITOC)

Postoperative adjuvant therapy for resectable early non-small cell lung cancer: A protocol for a systematic review and meta-analysis.

Background:Lung cancer is one of the most common malignant tumors, and non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer diagnosed. For patients with resectable early stage non-small cell lung cancer, routine postoperative adjuvant therapy can significantly prolong overall patient survival and reduce the risk of cancer recurrence. With the emergence and maturity of molecular targeted therapy and immunotherapy, the postoperative chemotherapy strategy of lung cancer patients has changed a lot. To evaluate the efficacy of postoperative adjuvant therapy (platinum-based chemotherapy, platinum-based chemotherapy plus molecular targeted therapy, platinum-based chemotherapy plus anti-angiogenic agents, or platinum-based chemotherapy plus immunotherapy) with or without radiotherapy for patients with NSCLC, we will conduct a systematic review and meta-analysis of the published or unpublished relevant randomized controlled trials.Methods:We will search PubMed (Medline), Embase, Google Scholar, Cancerlit, and the Cochrane Central Register of Controlled Trials for related studies published without language restrictions before June 20, 2019. Two review authors will search and assess relevant studies independently. Randomized controlled trials (RCTs) and quasi-RCTs studies will be included. We will perform subgroup analysis in different methods of postoperative adjuvant therapy for patients with resectable early NSCLC. Because this study will be based on published or unpublished records and studies, there is no need for ethics approval.Results:The results of this study will be published in a peer-reviewed journal.Conclusion:This study will comprehensively compare the efficacy of platinum-based chemotherapy with that of molecular targeted therapy and immunotherapy for patients after surgery with resectable early NSCLC. Since large-sample randomized trials meeting the inclusion criteria of this study may be insufficient, we will consider incorporating some high-quality small-sample-related trials, which may lead to high heterogeneity and affect the reliability of the results.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Platinum-based chemotherapy in metastatic prostate cancer with alterations in DNA damage repair genes.

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.

Identification and Characterization of Synthetic Viability with ERCC1 Deficiency in Response to Interstrand Crosslinks in Lung Cancer.

ERCC1/XPF is a DNA endonuclease with variable expression in primary tumor specimens, and has been investigated as a predictive biomarker for efficacy of platinum-based chemotherapy. The failure of clinical trials utilizing ERCC1 expression to predict response to platinum-based chemotherapy suggests additional mechanisms underlying the basic biology of ERCC1 in the response to interstrand crosslinks (ICLs) remain unknown. We aimed to characterize a panel of ERCC1 knockout (Δ) cell lines, where we identified a synthetic viable phenotype in response to ICLs with ERCC1 deficiency. We utilized the CRISPR-Cas9 system to create a panel of ERCC1Δ lung cancer cell lines which we characterized. We observe that loss of ERCC1 hypersensitizes cells to cisplatin when wild-type (WT) p53 is retained, whereas there is only modest sensitivity in cell lines that are p53mutant/null. In addition, when p53 is disrupted by CRISPR-Cas9 (p53*) in ERCC1Δ/p53WT cells, there is reduced apoptosis and increased viability after platinum treatment. These results were recapitulated in 2 patient data sets utilizing p53 mutation analysis and ERCC1 expression to assess overall survival. We also show that kinetics of ICL-repair (ICL-R) differ between ERCC1Δ/p53WT and ERCC1Δ/p53* cells. Finally, we provide evidence that cisplatin tolerance in the context of ERCC1 deficiency relies on DNA-PKcs and BRCA1 function. Our findings implicate p53 as a potential confounding variable in clinical assessments of ERCC1 as a platinum biomarker via promoting an environment in which error-prone mechanisms of ICL-R may be able to partially compensate for loss of ERCC1.See related commentary by Friboulet et al., p. 2369.

CD19+ tumor-infiltrating B-cells prime CD4+ T-cell immunity and predict platinum-based chemotherapy efficacy in muscle-invasive bladder cancer.

CD19+ tumor-infiltrating B-cells (CD19+ TIB) play a crucial role in tumorigenesis, but their clinical relevance in muscle-invasive bladder cancer (MIBC) remains unknown. This study aimed to investigate the prognostic value of CD19+ TIB for post-surgery survival and adjuvant chemotherapy response in MIBC. We assessed TIB by immunohistochemical staining of CD19 in 246 MIBC patients from Zhongshan Hospital and Shanghai Cancer Center. We evaluated the survival benefit of platinum-based chemotherapy according to CD19+ TIB. The mechanism underlying CD19+ TIB antitumor immunity was explored through the Cancer Genome Atlas (TCGA) dataset analysis and an in vitro Ag presentation assay. CD19+ TIB extensively infiltrated into the tumor stroma of MIBC. Adjuvant chemotherapy (ACT) led to a significantly increased benefit in the high CD19+ TIB MIBC patients (P = 0.003). In multivariate analysis, high CD19+ TIB MIBC patients had significantly longer OS with ACT in the discovery set (HR = 0.487, P = 0.038). TCGA gene expression analyses showed enrichment of adaptive immunity, T-cell-mediated immunity, and antigen-presentation signaling pathways in high CD19+ TIB MIBC patients. Moreover, CD19+ TIB co-localized with activated CD4+ TIT and expressed surface markers characteristic of antigen-presenting cells. Finally, an antigen-presentation assay demonstrated the antigen-presentation function of CD19+ TIB. CD19+ TIB was identified as an independent prognostic factor, which could predict for post-surgery survival and platinum-based ACT benefits in MIBC. CD19+ TIB serve as antigen-presenting cells (APCs) to activate CD4+ TIT in the tumor environment of MIBC.

PO-521 Expression of oestrogen receptor beta as a predictive marker of platinum and taxane-based chemotherapy in ovarian cancer patients

IntroductionPredictive markers of platinum-based chemotherapy efficacy in patients with ovarian cancer have been widely discussed in recent years. Oestrogen receptors (ER) are involved in regulation of proliferative factors responsible for tumour growth, so they could predict the effectiveness of anticancer chemotherapy. The aim of the study was to determine the predictive value of ER-beta expression in a cohort of ovarian cancer patients treated with platinum and taxanes. The level of ER-beta expression was correlated with progression-free survival and also with a number of disease relapses during 40 months of monitoring.Material and methodsThe quantitative immunofluorescence flow cytometry analysis was performed to detect ER-beta in 34 serous ovarian cancer surgical specimens. All the patients were treated with the first line platinum and taxane-based regimen. The primary anti-ER-beta (ab14C8) and the secondary antibodies (DyLight650, ab98729) were used for the analysis. The level of ER-beta expression was calculated by Kolmogorov-Smirnov statistical test as the ratio (%) of specifically fluorescent cells to the number of cells incubated only with secondary antibodies. Association of ER-beta expression levels with progression-free survival was analysed using the Kaplan-Meier method and log-rank tests.Results and discussionsER-beta were revealed in all tumour specimens tested and the median value of the expression level was 41,5%. Patients were dichotomized in groups with low and high level of ER-beta expression, below- and above-median value respectively. Significant differences were shown between these groups. First, median of progression-free survival was larger in the high-level expression group as compared to the low-level expression group – 25,5 vs 8 months. Second, the disease rate during 40 months of monitoring was lover in the high-level expression group as compared the low-level expression group – 6 vs 15 respectively.ConclusionA quantitative index of the ER-beta level expression in tumour tissue predicts the efficacy of the first line platinum and taxane-based chemotherapy in ovarian cancer patients. Progression-free survival was about 3.0 times longer and the number of the disease relapses during 40 months of monitoring was 1.5 times less in patients with high level of ER-beta expression. The study was supported in part by RSF 17-75-10212.

The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict efficacy of platinum-based chemotherapy in patients with metastatic triple negative breast cancer

Platinum salts are active against metastatic triple negative breast cancer (mTNBC), and biomarkers to predict their effectiveness are urgently needed. In recent years, the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have emerged as prognostic biomarkers in many malignancies, but their predictive role in platinum-treated mTNBC patients remains unexplored. We performed a retrospective, single centre study to evaluate the association between baseline NLR or PLR and progression free survival (PFS) of mTNBC patients treated with platinum-based chemotherapy. As a control population, we analysed data from patients with hormone receptor-positive HER2-negative (HR+ HER2−) metastatic breast cancer. Among 57 mTNBC patients treated with the carboplatin-paclitaxel or carboplatin-gemcitabine combination, high NLR and PLR were associated with significantly lower PFS at both univariate and multivariable analysis. Conversely, we did not find a significant association between NLR or PLR and the PFS of 148 patients in the control population. Our findings suggest that the NLR and PLR are predictive of benefit from platinum-containing chemotherapy specifically in mTNBC patients. If validated in larger prospective studies, these easy-to-measure parameters could be combined with emerging predictive biomarkers, such as BRCA 1/2 mutations, to improve the selection of mTNBC patients more likely to benefit from platinum-based chemotherapy.

Expression of UCP2 is associated with sensitivity to platinum-based chemotherapy for ovarian serous carcinoma.

The standard treatment for ovarian serous carcinoma is maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate for chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. Currently there are no reliable methods to determine or predict platinum resistance. Uncoupling protein 2 (UCP2) is widely expressed in cancer cells and regulates the production of mitochondrial reactive oxygen species (ROS). A reduction in ROS is associated with carcinogenesis and chemoresistance. Downregulation of UCP2 significantly causes increased cell death following chemotherapy. The present study investigated the association between UCP2 expression and platinum sensitivity. The study included 54 patients with ovarian serous carcinoma (FIGO stages III and IV) who were treated at Osaka City University Hospital between January 2005 and December 2012. Patients were divided into a platinum-sensitive group (n=27) and platinum-resistant group (n=27) based on the platinum-free interval, which was calculated from the time of last platinum administration to the time of recurrence. UCP2 expression in human ovarian serous carcinoma cells was inhibited by genipin, and changes in carboplatin sensitivity were examined. The UCP2 weighted score was lower in the platinum-sensitive group than in the platinum resistant-group (P=0.005). In addition, patients in the low UCP2 expression group were more sensitive to platinum-based chemotherapy than those in the high UCP2 expression group (P=0.001). Sensitivity to carboplatin was significantly increased when UCP2 was inhibited in human ovarian serous carcinoma cells in vitro. UCP2 expression may be a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma.

Platinum-Based Chemotherapy Plus Cetuximab in Patients With Recurrent or Metastatic Nasopharyngeal Cancer

Platinum-containing doublet chemotherapy regimens are generally considered the standard first-line systemic therapy for recurrent or metastatic (R/M) nasopharyngeal caner (NPC). Gemcitabine (GEM)+Cisplatin (CDDP) demonstrated significant improvement of both progression-free survival and overall survival over 5FU+CDDP for R/M NPC in a phase 3 study, leading to standard of care as first-line therapy for R/M NPC. Although the results of a phase 2 study of cetuximab (Cmab) in combination with carboplatin in patients with heavily pretreated NPC was reported, there was no available data for platinum-based chemotherapy plus Cmab as first-line therapy for R/M NPC. The objective of the currents study was to evaluate safety and efficacy of platinum-based chemotherapy plus Cmab in patients with R/M NPC. We conducted a retrospective review of patients with recurrent or metastatic NPC who were treated with platinum-based chemotherapy plus cetuximab during 2013 to 2017 at our institute. Treatment consisted of CDDP or carboplatin+5FU+Cmab(PFE) or paclitaxel+carboplatin+Cmab(PCE). Eleven patients were identified; patient characteristics were median age, 54.7 years (36-75); male /female 8/3; PS 0/1/2, 6/5/0; histology WHOI/II/III/ unknown, 2/3/3/3; number of prior chemotherapies 0/1/2/3 2/2/1; treatment regimen: PFE/PCE: 3/8. Of the 10 patients assessable for efficacy, 1 patient (10%) achieved complete response (CR), 3 patients (30%) with partial responses (PR), 5 patients (50%) with stable disease (SD), and 1 patient (10%) with progressive diseases (PD), in best response. Overall response rate (ORR) was 40% in all patients. The median progression-free survival (PFS) were 5.6 overall, 6.5 for patients treated with PFE, 5.4 months for patients treated with PCE, respectively. The median overall survival (OS) were 25.3 overall, 25.3 for patients treated with PFE, 25.8 months for patients treated with PCE, respectively. A patient who achieved CR has continued to receive Cmab maintenance for 42.3 months. Most common adverse events(AEs) were acne-like rash (81.8%), skin cracks (72.7%), and bone marrow suppression (54.5%). Most common grade 3 AEs were acne-like rash (1 patient) and althralgia (1 patient). Grade 4 AEs were infusion reaction (1 patient) and allergy due to carboplatin (1 patient). No treatment-related death was observed. Platinum-based chemotherapy plus Cmab demonstrated promising efficacy with ORR 40%, median PFS 5.6 months and OS of 25.3 months, with acceptable toxicities. Cmab in combination with gemcitabine plus CDDP, warrants further investigations.

Uterine serous carcinoma: Reassessing effectiveness of platinum-based adjuvant therapy

ObjectiveTwo randomized trials failed to demonstrate efficacy of platinum-based chemotherapy (PbCT) for uterine serous carcinoma (USC). Our objective was to reassess the value of PbCT for patients with microscopic residuum (R0). MethodsProgression-free survival (PFS) after surgery was analyzed for 409 patients and correlated with adjuvant therapies: vaginal brachytherapy (VBRT), external beam radiotherapy (EBRT), PbCT, or combinations. ResultsThe estimated 5-year PFS for stage I (n=209) USC was 65.1% for observation only; 90.7%, VBRT only; and 91.1%, PbCT±VBRT (85% received VBRT); VBRT significantly (P=.004) impacted PFS, but the added value of PbCT remains uncertain. Of 58 stage IIIC, PbCT-treated patients (±EBRT), 5-year PFS was 33.9%; most failures had a vascular disseminated component. Median PFS for 72 stage IV, PbCT-treated patients was 18.6months for R0; 8.0, R1≤1cm residual disease; and 4.6, R2>1cm (P=.008). The progression rate (PR) during 1 to 2year follow-up for R0 was similar to PR during 0–1year follow-up for R1 (P=.31), suggesting recurrences in patients with R0 disease before 2years are likely platinum resistant. PRs during follow-up were nearly identical for R0≥2years and R1≥1year (P=.95), presumably showing limited numbers of platinum-sensitive tumors. ConclusionsA comparison of PR for patients treated with PbCT for stage IV R0 and R1 disease suggested that a 1-year lag interval precedes clinical recognition of PbCT refractory/resistant R0 disease. Most patients treated with PbCT who had microscopic residuum had recurrences within 2years (across stages), emphasizing the need for more effective therapy.

Prediction of platinum-based chemotherapy efficacy in lung cancer based on LC–MS metabolomics approach

Lung cancer is the common cause of cancer-related death worldwide. Platinum-based chemotherapy is the cornerstone of treatment for lung cancer. Platinum sensitivity is a major possibility for effective cancer treatment. In this study, several potential biomarkers were identified for evaluating and predicting the response to platinum-based chemotherapy. LC–MS-based metabolomics was performed on plasma samples from 43 lung cancer patients with different chemotherapy efficacy. By combing multivariate statistical analysis, pathway analysis with correlation analysis, 8 potential biomarkers were significantly associated with platinum chemotherapy response. Moreover, a prediction model with these biomarkers involved in citric acid cycle, glutamate metabolism and amino acid metabolism, showed 100% sensitivity and 100% specificity for predicting chemotherapy response in a validation set. Interestingly, 2-hydroxyglutaric acid (2-HG) as an oncometabolite accumulated in lung cancer was remarkably elevated in the partial response (PR) patients. Collectively, our findings implicated that metabolomics can serve as a potential tool to select lung cancer patients that are more likely to benefit from the platinum-based treatment.

Efficacy of Platinum-Based Chemotherapy for Relapsed Small-Cell Lung Cancer after Amrubicin Monotherapy in Elderly Patients and Patients with Poor Performance Status

Background: Previous studies have shown amrubicin to be an effective first- or second-line treatment option for small-cell lung cancer (SCLC). However, there have been few studies reporting the efficacy of platinum-based chemotherapy after amrubicin therapy. We aimed to evaluate the efficacy of platinum-based chemotherapy as second-line treatment for elderly patients and those with SCLC with poor performance status (PS) previously treated with amrubicin monotherapy. Methods: The records of SCLC patients who received platinum-based chemotherapy as a second-line chemotherapy after first-line treatment with amrubicin monotherapy were retrospectively reviewed and the treatment outcomes were evaluated. Results: A total of 48 patients were enrolled in this study. Forty-one patients (85%) received carboplatin plus etoposide. The overall response rate was 39.6%. The median progression-free survival and overall survival were 3.7 and 7.6 months, respectively. The efficacy of the platinum-based regimen did not differ with the type of relapse after amrubicin monotherapy. The most common adverse events were hematological toxicities, including grade 3 or 4 neutropenia (38%), leukopenia (33%), and thrombocytopenia (10%). Conclusions: Platinum-based chemotherapy is potentially a valid treatment option for elderly patients or those with extensive-stage SCLC with poor PS as second-line chemotherapy, who progressed after first-line treatment with amrubicin monotherapy.

TBX2 expression is associated with platinum-sensitivity of ovarian serous carcinoma.

The standard treatment for ovarian serous carcinoma comprises maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate to chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. At present there are no reliable methods to determine or predict platinum resistance. T-box 2 (TBX2) is widely expressed in cancer cells and is involved in embryonic development and cell cycle regulation. TBX2 enables cells to bypass senescence through its ability to repress the cell cycle regulators p21 and p14ARF; silencing TBX2 induces senescence. Ectopic expression of TBX2 is associated with conferred resistance to the DNA-damaging chemotherapeutic drugs cisplatin and doxorubicin. In the present study the association between TBX2 expression and platinum sensitivity was investigated. A total of 54 patients with ovarian serous carcinoma (FIGO stages III and IV) were treated at Osaka City University Hospital (Osaka, Japan) from January 2005 to December 2012. Patients were divided into platinum-sensitive (n=27) and resistant (n=27) groups, according to the platinum-free interval calculated from the last platinum administration to the time of recurrence. TBX2 expression in human ovarian serous carcinoma cells was inhibited by a TBX2-specific siRNA and changes in cisplatin and carboplatin sensitivity were determined. The TBX2-weighted score was significantly lower in the platinum-sensitive group than the platinum-resistant group (P=0.005) and the low TBX2 expression group was significantly more sensitive to platinum-based chemotherapy (P=0.004). Sensitivity to cisplatin and carboplatin significantly increased when TBX2 expression was inhibited in human ovarian serous carcinoma cells in vitro (P<0.05). TBX2 expression may serve as a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma.

Caspase 8 polymorphisms contribute to the prognosis of advanced lung adenocarcinoma patients after platinum-based chemotherapy

ABSTRACTLung cancer is the leading cause of cancer deaths in China, and about 60% of the cases are diagnosed with histological adenocarcinoma. The caspase 8 (CASP8) gene is a critical initiator of the extrinsic apoptosis pathway. To explore the relationship between tagSNPs or haplotypes of CASP8 and the efficacy of platinum-based chemotherapy in advanced lung adenocarcinoma patients of China, we recruited 555 advanced adenocarcinoma patients. We extracted the genomic DNA from patients' peripheral blood samples and sequenced tagSNPs of CASP8. We calculated the individual haplotype of CASP8 frequencies using the PHASE 2.0 program. The association between CASP8 tagSNPs and overall survival (OS) was calculated by univariate and multivariate Cox regression analysis. A univariate logistic regression analysis was done to analyze the CASP8 tagSNPs and the toxicity of platinum-based chemotherapy. The same statistical methods were used for exploring haplotypes of CASP8. Rs3769821 and rs1045494 of CASP8 were independent prognosis factors for overall survival (OS) using multivariate Cox's regression models. For the haplotype of the 7 tagSNPs, haplotype AGGAAAGA was correlated with the efficacy of platinum-based chemotherapy. The polymorphisms of CASP8, rs7608692, and haplotype AGAACAG correlated with neutropenia toxicity. The haplotype GGGGAAA was associated with thrombocytopenia toxicity. We conclude that the polymorphisms of CASP8 contribute to the prognosis of advanced lung adenocarcinoma and influence the quality of life and survival.

Prognostic and Predictive Value of O6-methylguanine Methyltransferase for Chemotherapy in Patients with Muscle-Invasive Bladder Cancer.

DNA repair genes are potential biomarkers for chemotherapy in muscle-invasive bladder cancer (MIBC). O6-methylguanine methyltransferase (MGMT) is involved in DNA repair and is found to affect the efficacy of platinum-based chemotherapy. However, the prognostic or predictive value of MGMT expression in chemotherapy for MIBC is unknown. Immunohistochemical staining for MGMT was performed in paraffin-embedded tumor tissue of high-grade MIBC patients who underwent cystectomy in two independent cohorts [n=74 for Fudan University Shanghai Cancer Center (FUSCC) cohort and n=115 for Zhongshan Hospital (ZS) cohort]. MGMT messenger RNA (mRNA) analysis was conducted using patients' clinical and fragments per kilobase of exon model per million mapped fragments mRNA data from The Cancer Genome Atlas (TCGA) database (n=245). In our cohorts, high MGMT expression was significantly correlated with shorter overall survival (OS) in patients with platinum-based adjuvant chemotherapy [hazard ratio (HR) 2.386, p=0.048; HR 2.920, p=0.007; HR 2.324, p=0.004, respectively, in FUSCC, ZS, and combination sets], but not in patients without chemotherapy. These findings were corroborated by the TCGA set (HR 1.952 and 0.697 for patients with and without chemotherapy, respectively). The chemotherapy-MGMT interaction for OS was significant in both the surgery set (p=0.045) and TCGA set (p=0.034). We demonstrated that high MGMT expression is an independent poor prognostic factor in MIBC patients with platinum-based adjuvant chemotherapy, but not in patients without chemotherapy. MGMT expression may be a potential predictor for administration of adjuvant chemotherapy.