First-line Treatment Of Ovarian Cancer Research Articles

Erastin synergizes with cisplatin via ferroptosis to inhibit ovarian cancer growth in vitro and in vivo.

Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment or serious side effects often occurs in ovarian cancer, and thus, there is an urgent need for effective and combined therapies to overcome such obstacles. In the present study, we aimed to uncover synergistic effects between erastin and cisplatin (CDDP) in inhibiting ovarian cancer cell growth by inducing ferroptosis in vitro and in vivo. We performed a CCK-8 assay to detect cell viability in response to erastin alone or in combination with cisplatin and provided further confirmation by western blotting analysis. Transmission electron microscopy and flow cytometry analysis were used to depict the characteristics of ferroptosis. In addition, an ovarian cancer tumor xenograft was built to verify the effects in vivo. CDDP induced multiple modes of cell death-including ferroptosis in ovarian cancer cell lines. Mechanistically, erastin triggered ferroptosis and increased the levels of reactive oxygen species (ROS) so as to augment the cytotoxic effect of cisplatin. Combination therapy based on CDDP and erastin appeared to maximize the therapeutic effects while minimizing side effects in ovarian cancer both in vitro and in vivo. Collectively, our results indicate that erastin works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

Nanog-mediated stem cell properties are critical for MBNL3-associated paclitaxel resistance of ovarian cancer.

Paclitaxel (PTX) is the standard first-line treatment of ovarian cancer, but its efficacy is limited by multidrug resistance. Therefore, it is crucial to identify effective drug targets to facilitate PTX sensitivity for ovarian cancer treatment. Seventy PTX-administrated ovarian cancer patients were recruited in this study for gene expression and survival rate analyses. Muscleblind-like-3 (MBNL3) gain-of-function and loss-of-function experiments were carried out in ovarian cancer cells (parental and PTX-resistant) and xenograft model. Cancer cell viability, apoptosis, spheroids formation, Nanog gene silencing were examined and conducted to dissect the underlying mechanism of MBNL3-mediated PTX resistance. High expression of MBNL3 was positively correlated with PTX resistance and poor prognosis of ovarian cancer. MBNL3 increased cell viability and decreased apoptosis in ovarian stem-like cells, through upregulating Nanog. This study suggests the MBNL3-Nanog axis is a therapeutic target for the treatment of PTX resistance in ovarian cancer management.

Abstract 4084: A DGKA-cJUN-WEE1 signaling axis provides platinum resistance in ovarian cancer

Abstract Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. Here, we report a unique platinum resistance mechanism that is mediated by a lipid messenger, phosphatidic acid (PA), in ovarian cancer. A phospho-proteomics screen revealed that PA, which is predominantly produced by diacylglycerol kinase alpha (DGKA) in ovarian cancer, activates the transcription factor c-JUN. DGKA and PA facilitate JNK recruitment to c-JUN and nuclear localization leading to its activation upon cisplatin exposure. Through a genomic screen, we identified that activated c-JUN enhances expression of WEE1 and consequently prevents cells from aberrant cell cycle progression upon cisplatin exposure. DGKA-cJUN-WEE1 signaling was elevated in tumors derived from ovarian cancer patients who did not respond to platinum-based therapy compared to tumors from patients who responded to treatment. Our study demonstrates how lipid metabolism, kinase signaling, and gene regulatory systems are intertwined to direct cisplatin resistance in ovarian cancer. Citation Format: Jie Li, Chaoyun Pan, Austin C. Boese, Anna Umano, Sumin Kang. A DGKA-cJUN-WEE1 signaling axis provides platinum resistance in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4084.

Weekly Carboplatin and Paclitaxel: A Retrospective Comparison with the Three-Weekly Schedule in First-Line Treatment of Ovarian Cancer.

Conventional first-line combination therapy for ovarian cancer comprises 6 cycles of adjuvant or neoadjuvant carboplatin (AUC5-6) with paclitaxel (175 mg/m2 ) every 3 weeks (PC-3W). Weekly scheduling of paclitaxel may maximize its antiangiogenic effect and reduce adverse effects. We compared the efficacy and safety of PC-3W with a modified protocol of weekly paclitaxel 80 mg/m2 and weekly carboplatin AUC2 administered on days 1, 8, and 15 in a 28-day cycle (i.e., with 1 week off-treatment [PC-W]). Medical records of consecutive patients treated between 2000 and 2018 were reviewed; 707 patients were analyzed for demographic and clinical characteristics, effectiveness and toxicity. PC-3W was administered to 402 patients (median age, 60.5 years) and PC-W to 305 patients (median age, 62.5 years). Most patients (91.4%) were diagnosed at stage III-IV. Notwithstanding a higher proportion of residual disease and older patients in the PC-W group, median progression-free survival was 21.4 months and 13.2 months for PC-W and PC-3W, respectively; median overall survival was 75.2 and 54.0 months for PC-W and PC-3W, respectively. Cox proportional hazards model indicated improved survival for patients treated with PC-W (hazard ratio, 0.54). Similar results were observed for older patients diagnosed at ≥75 years. PC-W demonstrated a better safety profile, with lower incidence of neuropathy, neutropenia, and alopecia. PC-W is as active and better tolerated than the standard PC-3W regimen. PC-W may serve as an alternative option for elderly or frail patients. Weekly scheduling of paclitaxel 80 mg/m2 and carboplatin AUC2, administered on days 1, 8, and 15 in a 28-day cycle (PC-W) for first-line therapy for advanced ovarian cancer, is as active and better tolerated than the standard regimen of carboplatin and paclitaxel (175 mg/m2 ) every 3 weeks (PC-3W). It is possible that the weekly holiday on day 21 in the PC-W regimen may ensure better completion rates (which may result in treatment delays for toxicity in PC-3W). The results of this retrospective analysis highlight the weekly regimen as a valid treatment option, especially for elderly patients and those with significant comorbidities.

DGKA Provides Platinum Resistance in Ovarian Cancer Through Activation of c-JUN-WEE1 Signaling.

Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. The goal of our study is to decipher the mechanism by which a metabolic kinase, diacylglycerol kinase alpha (DGKA), confers platinum resistance in ovarian cancer. Metabolic kinase RNAi synthetic lethal screening was used to identify a cisplatin resistance driver in ovarian cancer. DGKA variants were used to demonstrate the need for DGKA activity in cisplatin resistance. Phospho-proteomic and genomic screens were performed to identify downstream effectors of DGKA. Therapeutic efficacy of targeting DGKA was confirmed and clinical relevance of DGKA signaling was validated using ovarian cancer patient-derived tumors that had different responses to platinum-based therapy. We found that platinum resistance was mediated by DGKA and its product, phosphatidic acid (PA), in ovarian cancer. Proteomic and genomic screens revealed that DGKA activates the transcription factor c-JUN and consequently enhances expression of a cell-cycle regulator, WEE1. Mechanistically, PA facilitates c-JUN N-terminal kinase recruitment to c-JUN and its nuclear localization, leading to c-JUN activation upon cisplatin exposure. Pharmacologic inhibition of DGKA sensitized ovarian cancer cells to cisplatin treatment and DGKA-c-JUN-WEE1 signaling positively correlated with platinum resistance in tumors derived from patients with ovarian cancer. Our study demonstrates how the DGKA-derived lipid messenger, PA, contributes to cisplatin resistance by intertwining with kinase and transcription networks, and provides preclinical evidence for targeting DGKA as a new strategy in ovarian cancer treatment to battle cisplatin resistance.

Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer

The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types. To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer. In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials. Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm. Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019. Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS. This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.

Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo

BackgroundCisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo.ResultsWe performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone.ConclusionCollectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

1014P - Response to chemotherapy in ovarian cancer (OC) patients with or without prior breast cancer (BC), stratified by BRCA mutation (BRCAm) status

BackgroundWomen with OC due to an underlying BRCAm have enhanced responses to platinum and often improved progression free survival. BRCAm carriers also have an increased risk of BC, which often predates OC and may impact later treatment response. MethodsWomen with OC treated at The Royal Marsden Hospital between 01/06/13 and 31/5/17 with known BRCAm status were identified from the electronic patient record. The primary endpoint was progression free survival (PFS) after first line treatment for OC, stratified for BRCAm and BC status. Secondary endpoints were time to second subsequent treatment (TSST) and type of BRCA mutation (BRCA1 vs BRCA2). Results575 patients were identified, 502 high grade (HG), 73 low grade (LG) OC. Histology was HG serous (77%), endometroid (10%), clear cell (5%), LG serous (4%), other (4%). 158 (27%) had a BRCAm, 92 (58%) BRCA1 and 66 (42%) BRCA2. Mean age of OC diagnosis was 59 (19-98) yrs. Prior BC was noted in 79 patients – 51 BRCAm, 28WT; 21 patients had >1 BC (14 BRCA, 7WT). Mean age of first BC diagnosis was 50 yrs (30-75). Median PFS (mths) was 19.6 (BC, WT) vs 23.6 (no BC, WT) vs 25.4 (BC, BRCAm) vs 27.1 (no BC, BRCAm), p=0.08. TSST(mths) was significantly different at 23.1 (BC, WT) vs 30 (no BC, WT) vs 34 (BC, BRCAm) vs 42.6 (no BC, BRCAm), p=0.02. There was no significant difference in PFS between those who did/did not receive chemotherapy for prior breast cancer; nor between those with a BRCA1 vs BRCA2 mutation. ConclusionsWithin the limits of a retrospective audit, there was no significant difference in PFS for women with OC irrespective of prior BC diagnosis or BRCAm status, but there was a significant difference in TSST. A similar trend was seen in both groups, with poorest PFS/TSST in those with prior BC/BRCA WT; and best PFS/TSST in those with no prior BC/BRCAm. Prior BC diagnosis may be another factor in response to OC chemotherapy. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Olaparib maintenance for first-line treatment of ovarian cancer:will SOLO1 reset the standard of care?

Maintenance therapy with PARP inhibitors has heralded a new era in the management of recurrent epithelial ovarian cancer. The greatest effect is seen in women with BRCA1/2 tumors but those without this mutation also benefit. However, in most patients, the drugs eventually fail to prevent progression, so alternative strategies are needed. The SOLO1 trial randomized women with BRCA1/2-mutated advanced ovarian cancer to olaparib or placebo maintenance after first-line chemotherapy. Olaparib significantly improved progression-free survival to a degree that has not been seen in other first-line trials in ovarian cancer. This landmark trial is likely to change practice for this group of women. Here, we focus on the SOLO1 results in the context of the current management of advanced ovarian cancer.

Inhibition of XIAP increases carboplatin sensitivity in ovarian cancer

PurposeCarboplatin is a first-line treatment for ovarian cancer. However, most patients develop resistance and undergo disease recurrence. This study aims to explore the relationship between the expression of X-linked inhibitor of apoptosis protein (XIAP) and carboplatin sensitivity in ovarian cancer.Patients and methodsWe examined the expression of XIAP in ovarian cancer by immuno-chemistry. Next, we investigated the role of XIAP in regulating carboplatin sensitivity in ovarian cancer ES2 and 3AO cells through Cell Counting Kit-8 cell viability assay and fluorescein isothiocyanate-Annexin V/propidium iodide apoptosis assay. Expression of apoptotic effectors was measured by Western blot.ResultsThe immunochemistry results showed that high XIAP expression levels inversely correlated with carboplatin response (P=0.03) and progression-free survival (P=0.0068) in patients with ovarian cancer. Knockdown of XIAP repressed the cell viabilities in the carboplatin-treated cells and increased carboplatin-induced caspase activation. In summary, our data show that XIAP mediates carboplatin sensitivity of ovarian cancer.ConclusionIn summary, our data show that XIAP mediates carboplatin sensitivity of ovarian cancer and XIAP may be a novel target for the treatment of carboplatin-resistant ovarian cancer.

STAT3 regulated miR-216a promotes ovarian cancer proliferation and cisplatin resistance.

Cisplatin is the first-line treatment for ovarian cancer. However, the clinical outcome of cisplatin treatment in ovarian cancer is hindered by cancer resistance. Here we aim to explore the role and mechanism of miR-216a in the cisplatin resistance of ovarian cancer. The effects of miR-216a overexpression and inhibition on ovarian cell proliferation, colony formation, and cisplatin resistance were investigated by MTT assay and soft agar colony formation assay. Bioinformatics analyses using TargetScan and rVista, qPCR, and luciferase assay were also used to explore and verify downstream effectors and regulators of miR-216a. Proliferation, colony formation, and cisplatin resistance of ovarian cancer cells are promoted by miR-216a overexpression but inhibited by miR-216a inhibition. PTEN is a direct target of miR-216a and PTEN expression antagonizes the tumor-promoting function of miR-216a. STAT3 is a regulator of miR-216a, and PTEN is also regulated by STAT3. miR-216a up-regulation is associated with cisplatin resistance in ovarian cancer and this effect is mediated by PTEN. STAT3 is a regulator of miR-216a. Strategies that inhibit miR-216a is a potential strategy for overcoming the cisplatin resistance in ovarian cancer.

Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance.

Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2-STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11-JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS-IL-11-JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.

Could HE4 level measurements during first-line chemotherapy predict response to treatment among ovarian cancer patients?

BackgroundThis study assessed the prognostic value of HE4 marker measurements at various stages of first-line chemotherapy for ovarian cancer.MethodsThe study consisted of 90 ovarian cancer patients, including 48 women undergoing primary surgical treatment and 42 patients qualified for neoadjuvant chemotherapy. Each patient underwent HE4 and CA 125 level measurements at the time of diagnosis and subsequently as follows: after surgical treatment, after the third course of adjuvant chemotherapy, before interval cytoreductive surgery and after chemotherapy. The HE4 value was assessed based on the PSF, OS, DFS, surgical outcome, two-year survival and platinum sensitivity.ResultsPreoperative HE4 levels were a predictor of platinum sensitivity (AUC– 0.644; p = 0.035) and DFS (AUC = 0.637; p = 0.0492). A univariate logistic regression analysis showed that serum HE4 significantly correlated with PFS (baseline results over median HR = 2.96, p = 0.0009; baseline over 75 percentile HR = 2.44, p = 0.0062; normalization after treatment HR = 0.46, p = 0.0125; 50% reduction before IDS HR = 0.64, p = 0.0017). In the multivariate analysis, normalization after treatment and 50% reduction before IDS significantly influenced the PFS (HR = 0.29, p = 0.00008; HR = 0.23, p = 0.0024). The HE4 levels also correlated with the OS as follows: values below the median (HR = 1.88, p = 0.0087), normalization after chemotherapy (HR = 0.08, p = 0.0003), and 50% reduction before IDS (HR = 0.39, p = 0.0496).ConclusionsThe significant effect of the normalization of the HE4 marker after therapy and 50% reduction of HE4 levels before interval cytoreductive surgery on PFS and OS confirmed that HE4 might be an independent prognostic factor of treatment response. HE4 measurements performed during first-line treatment of ovarian cancer may have prognostic significance.

Abstract 5031: Distribution of single nucleotide polymorphisms related to paclitaxel and carboplatin toxicity in ovarian cancer patients

Abstract Introduction: Standard first-line treatment for ovarian cancer consists in the combined use of taxanes and platinum, with neuropathies and neutropenia the most frequent and complex adverse drug reactions (ADRs) requiring clinical management. These adverse effects may be related to differing levels of drug transport and metabolism brought about by intrinsic genetic characteristics of the patients. Single nucleotide polymorphisms (SNPs) are now recognized as key factors in the variability of drug response. In a cohort of Chilean ovarian cancer patients we analyzed the frequencies of several SNPs previously reported to be associated with paclitaxel and carboplatin ADRs. Methods: Blood samples were obtained with informed consent from adult ovarian cancer patients (n = 120). DNA was extracted and SNPs within the ABC transporter and CYP P450 gene families were genotyped. High specificity Taqman probes were used. Results: Four SNPs associated with risk of ADR within the ABC transporter family showed genotypic frequencies ranging between 0 - 23%. Frequencies for the ADR-associated variants in the CYP P450 family were 4 - 90%. Finally, for the CYP2C8 enzyme, whose function is essential in paclitaxel metabolism, the frequencies of risk-associated SNPs ranged from 2.10% to 13.6%. Conclusions: SNPs associated with paclitaxel and carboplatin ADRs are highly prevalent in the Chilean population of ovarian cancer patients studied. The identification of these variants may help avoid severe ADRs associated with chemotherapy regimes. Funding: CORFO 13CTI21526-P6 & 13IDL2-18608 Citation Format: Miguel Cordova, Maria L. Bravo, Isidora Arriagada, Elisa Cumsille, Luis Quiñones, Erasmo Bravo, Raimundo Correa, Juan E. Leiva, Cesar Paredes, Mauricio Cuello, Carolina Ibañez, Marcelo Garrido, Gareth I. Owen. Distribution of single nucleotide polymorphisms related to paclitaxel and carboplatin toxicity in ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5031. doi:10.1158/1538-7445.AM2017-5031

Bevacizumab as first-line treatment of ovarian cancer: strengths and weaknesses of subgroup analyses

Bevacizumab is approved as first-line treatment for ovarian cancer, in combination with carboplatin-paclitaxel, in patients with FIGO IIIb or IV disease, and as maintenance therapy. The results of subgroup analyses of data from the ICON7 study have resulted in bevacizumab use being restricted to “high-risk” patients in several countries. While a goal of obtaining as much information as possible from clinical trial data is understandable, there are also a number of limitations associated with subgroup analyses. Interpretation can be limited by the multiplicity of statistical tests (increasing the risk of false positive findings) and by low statistical power (increasing the chance of false negative results). In addition, the credibility of subgroup analyses is improved if they are restricted to the primary study outcome and limited to a small number of predefined patient subgroups. Overall, subgroup findings should be considered exploratory and hypothesis-generating. The subgroup analysis in ICON7 had a number of limitations, including post hoc definition of “high-“ and “lowrisk” groups, and questionable applicability of these definitions to clinical practice. Use of residual disease as a determinant of risk status is also problematic. Excessive emphasis on the role of subgroup analyses may lead to misunderstanding of the true results generated by the overall trial data, and support the incorrect selection of patients to be treated with the new or experimental therapy. Caution should be used in translating results of subgroup analysis to clinical practice guidelines.

Genetic variation of CYP3A5 influences paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients.

Combination chemotherapy with platinum and taxane is the first-line treatment for ovarian cancer. The dose-limiting toxicities of these drugs include neuropathy, leukopenia, and neutropenia, but they exhibit substantial interindividual variability. This study investigated the relationship between CYP3A5 polymorphisms and paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Seventy-five patients with epithelial ovarian cancer were recruited. After combination chemotherapy, genotype analysis was conducted, and toxic effects were evaluated according to the Common Toxicity Criteria. A significant association was found between myelosuppression and the CYP3A5*3 genotype. CYP3A5*3/*1 patients showed a significantly higher risk of developing leukopenia (P < .001; Pearson's χ(2) test) and neutropenia (P < .001; Pearson's χ(2) test) than CYP3A5*3*3 patients. CYP3A5*3/*3 patients had significantly higher median leukocyte and neutrophil nadir counts than CYP3A5*3*1 patients (P < .001, Mann-Whitney U test). However, we did not observe an association between neuropathy and CYP3A5*3 in this study (P =.64; Pearson's χ(2) test). This is the first study to verify the influence of CYP3A5 polymorphisms on paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Our findings suggest that interindividual variability in paclitaxel/carboplatin-induced myelosuppression can be predicted by CYP3A5*3 genotyping and that incorporation of CYP3A5*3 genetic data in treatment selection could help to reduce myelosuppression events, thereby individualizing paclitaxel/carboplatin pharmacotherapy.

Abstract CT204: Preliminary results from PiSARRO, a phase Ib/II study of APR-246, a mutant p53 reactivating small molecule, in combination with standard chemotherapy in platinum-sensitive ovarian cancer

Abstract APR-246 (PRIMA-1MET) is the first clinical-stage compound that reactivates mutant p53. This phase Ib part of a proof of concept study aims to determine the recommended phase II dose (RP2D) of APR-246 in combination with carboplatin and pegylated liposomal doxorubicin (PLD) in platinum sensitive High Grade Serous Ovarian Cancer (HGSOC). Despite high response rates from carboplatin in combination with paclitaxel in first-line treatment of ovarian cancer, most patients relapse and develop resistance. Partially platinum sensitive patients relapse between 6 and 24 months and are commonly treated with second -line carboplatin and PLD (Pujade-Lauraine et al. JCO, 2010). The mechanisms of platinum resistance are multifactorial; two of the main causes are mutations in p53 and increased levels of intracellular glutathione. Like the analog PRIMA-1, APR-246 is a pro-drug that is converted to the active form MQ, which restores wild type conformation to mutant p53 (Lambert et al. Cancer Cell, 2009). In addition, APR-246 has been shown in vitro to reduce glutathione levels, resensitize cancer cells to platinum drugs, and induce ROS levels and ER stress (Mohell et al. Abstract #1801, AACR 2014; Lambert et al. Oncogene, 2010). In the first-in-human phase Ia study, APR-246 monotherapy was found to have a satisfactory safety and pharmacokinetic profile allowing it to be combined with full dose chemotherapy (Lehmann et al., JCO, 2012). The ongoing phase Ib/II study is enrolling patients with recurrent platinum sensitive HGSOC with positive p53 staining on immunohistochemistry. The phase Ib study has a 3+3 dose escalation design with 3 planned dose levels. APR-246 is administered as a 6h i.v. infusion on 4 consecutive days every 4 weeks. On day 4, APR-246 is given concomitantly with carboplatin AUC 5 and PLD 30 mg/m2. In the phase II part, 164 patients will be randomized to standard chemotherapy with or without APR-246. To date patients have been enrolled to all 3 dose cohorts. One DLT of ruptured diverticulum occurred at the 2nd dose level. No new safety concerns have emerged. The pharmacokinetic profile has not indicated any interaction between APR-246 and the chemotherapy. The first 3 patients have completed their therapy and are now in follow up. All 3 had partial response (PR) by RECIST 1.1 and 2/2 evaluable also had PR by GCIC. In conclusion, early results from the ongoing clinical study are encouraging and support the continued development of APR-246 in the phase II part of the study comparing platinum based standard chemotherapy with or without APR-246 in patients with HGSOC with mutant p53. Preliminary results from all three dose levels and the RP2D will be presented at the meeting. Citation Format: Mikael von Euler, Klas G. Wiman, Hani Gabra, James D. Brenton, Bristi Basu, Ignace Vergote, Charlie Gourley, Austin Smith, Jessica Alfredsson, Nina Mohell, John A. Green. Preliminary results from PiSARRO, a phase Ib/II study of APR-246, a mutant p53 reactivating small molecule, in combination with standard chemotherapy in platinum-sensitive ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT204. doi:10.1158/1538-7445.AM2015-CT204

Risk of Ovarian Cancer Relapse score: a prognostic algorithm to predict relapse following treatment for advanced ovarian cancer.

ObjectiveThe aim of this study was to construct a prognostic index that predicts risk of relapse in women who have completed first-line treatment for ovarian cancer (OC).MethodsA database of OC cases from 2000 to 2010 was interrogated for International Federation of Gynecology and Obstetrics stage, grade and histological subtype of cancer, preoperative and posttreatment CA-125 level, presence or absence of residual disease after cytoreductive surgery and on postchemotherapy computed tomography scan, and time to progression and death. The strongest predictors of relapse were included into an algorithm, the Risk of Ovarian Cancer Relapse (ROVAR) score.ResultsThree hundred fifty-four cases of OC were analyzed to generate the ROVAR score. Factors selected were preoperative serum CA-125, International Federation of Gynecology and Obstetrics stage and grade of cancer, and presence of residual disease at posttreatment computed tomography scan. In the validation data set, the ROVAR score had a sensitivity and specificity of 94% and 61%, respectively. The concordance index for the validation data set was 0.91 (95% confidence interval, 0.85-0.96). The score allows patient stratification into low (<0.33), intermediate (0.34–0.67), and high (>0.67) probability of relapse.ConclusionsThe ROVAR score stratifies patients according to their risk of relapse following first-line treatment for OC. This can broadly facilitate the appropriate tailoring of posttreatment care and support.

ICON8: An international randomized trial comparing two dose-dense regimens, 3-weekly carboplatin plus weekly paclitaxel (CwT), and weekly carboplatin-paclitaxel (wCwT), to standard 3-weekly treatment in women with newly diagnosed ovarian, fallopian tube, and primary peritoneal cancer.

TPS5611 Background: Three-weekly intravenous carboplatin-paclitaxel (CT) is a standard of care for the first-line treatment of ovarian cancer. Dose-dense weekly (w) CwT improved survival in the JGO...

Serum HE4, CA125, YKL-40, bcl-2, cathepsin-L and prediction optimal debulking surgery, response to chemotherapy in ovarian cancer.

BackgroundThe most important prognostic factor in the ovarian cancer is optimal cytoreduction. The neoadjuvant chemotherapy, an only optional method of treatment in this case and is still the subject of debate. The object of this study was to evaluate the usefulness of markers: CA 125, HE4, YKL-40 and bcl-2 as well as cathepsin L in predicting optimal cytoreduction and response to chemotherapy.MethodsSera were secured preoperatively. The division into groups was performed retrospectively depending on the method of treatment (surgery vs neoadjuvant chemotherapy) as well as on response to chemotherapy (sensitive vs resistant vs refractory). Comparisons were made between groups, and the diagnostic usefulness of tested proteins was examined.ResultsWe found that statistically significant differences between primary operated patients and patients undergoing neoadjuvant chemotherapy were applicable only to the tumour markers (CA125 1206.79 vs 2432.38, p = 0.000191; HE4 78.87 vs 602.45, p = 0.000004; YKL-40 108.13 vs 203.96, p = 0.003991). Cathepsin-L and Bcl-2 were statistically insignificant. The cut-off point values were determined for the CA 125 (345 mIU/ml), HE4 (218.43 pmol/L) and YKL-40 (140.9 ng/ml). The sensitivity, specificity, PPV and NPV were as follows: CA125 (83.3%; 75%; 80.6%; 78.3%), HE4 (86.6%; 91.3%; 92.9%; 84%) and YKL-40 (75%; 83.3%; 84%; 74.1%).ConclusionAmong the tested proteins the HE4 marker appears to be helpful in forecasting of optimal cytoreduction and possibly also of the prediction of response to platinum analogues used in first-line treatment of ovarian cancer.