Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease.

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Measurements of adiposity as prognostic biomarkers for survival with anti-angiogenic treatment in epithelial ovarian cancer: An NRG Oncology/Gynecologic Oncology Group ancillary data analysis of GOG 218.

OBJECTIVE: Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial. METHOD: Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT) + placebo (P) → P or CT + BEV → BEV. RESULTS: After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (p = 0.981). There was a non-significant 0.1% (p = 0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (p = 0.890) or VFA (p = 0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (p = 0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (p = 0.606). CONCLUSION: Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor.

Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: an NRG Oncology/Gynecologic Oncology Group ancillary data study.

OBJECTIVE: To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors. METHODS: Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (>10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC). RESULTS: The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p<0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors. CONCLUSIONS: The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.

Harmonising clinical trials within the Gynecologic Cancer InterGroup: consensus and unmet needs from the Fifth Ovarian Cancer Consensus Conference.

The Gynecologic Cancer InterGroup (GCIG) Fifth Ovarian Cancer Consensus Conference (OCCC) was held in Tokyo, Japan from 7 to 9 November 2015. It provided international consensus on 15 important questions in 4 topic areas, which were generated in accordance with the mission statement to establish 'International Consensus for Designing Better Clinical Trials'. The methodology for obtaining consensus was previously established and followed during the Fifth OCCC. All 29 clinical trial groups of GCIG participated in program development and deliberations. Draft consensus statements were discussed in topic groups as well as in a plenary forum. The final statements were then presented to all 29 member groups for voting and documentation of the level of consensus. Full consensus was obtained for 11 of the 15 statements with 28/29 groups agreeing to 3 statements, and 27/29 groups agreeing to 1 statement. The high acceptance rate of the statements among trial groups reflects the fact that we share common questions, and recognise important unmet needs that will guide future research in ovarian cancer.

Fifth Ovarian Cancer Consensus Conference: individualized therapy and patient factors.

This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.

Optimal primary therapy of ovarian cancer.

BACKGROUND: Epithelial ovarian cancer continues to have the highest case-fatality ratio of all gynecologic cancers, in spite of ongoing advances in risk-assessment, genomics, tumor biology, cytoreductive surgery, chemotherapy, and molecular-targeted interventions. Primary treatment options for advanced-stage disease not only should reflect current best standards, but also need to be tailored for individual patients, with consideration of local resources. METHODS: Formulation of recommendations for optimal primary therapy based on a selective review of data from completed randomized trials, analysis of ongoing trials, and integration with current tumor biology, within the context of individualized clinical care. Recommendations were presented for discussion during an international meeting of experts in ovarian cancer treatment. RESULTS: Key recommendations include full adjuvant therapy for early-stage high-grade serous cancer; tailored utilization of neoadjuvant chemotherapy based on patient comorbidities, extent of disease, and likelihood of achieving optimal surgical cytoreduction; preferred utilization of carboplatin with weekly paclitaxel as primary therapy; consideration of intraperitoneal cisplatin-based therapy in appropriate patients; avoidance of maintenance chemotherapy; lack of necessity for bevacizumab during primary chemotherapy and primary maintenance; acknowledgement of research opportunities and priorities. CONCLUSIONS: Integrated multidisciplinary care, including cytoreductive surgery and platinum-based chemotherapy, remain central to the optimal management of women with advanced-stage ovarian cancer. However, even with recent technical advances, the impact on disease-related mortality is limited, and more attention will be focused on the early integration of research, particularly with neoadjuvant chemotherapy and interval cytoreductive surgery.

Do we have a new standard in suboptimal debulked disease?

Treatment options for patients with high-risk advanced-stage ovarian cancer continue to evolve, including consideration of neoadjuvant chemotherapy (NACT), timing of cytoreductive surgery, utilization of intraperitoneal (IP) chemotherapy, adoption of dose-dense weekly paclitaxel (Taxol), addition of maintenance chemotherapy, and incorporation of bevacizumab. Overall, the proportion of patients with suboptimal residual disease has declined, partly as a result of more aggressive primary surgery, and partly through selection of patients for delayed surgery following NACT. However, the risk of recurrence in this population remains high, and treatment decisions need to be individualized, with consideration of clinical goals, avoidance of treatment-related toxicity, control of disease-related symptoms, and minimization of any negative impact on the quality of life. Innovative trials are needed to evaluate early predictors of primary platinum resistance and facilitate the development of non-platinum alternative treatment regimens.

The addition of new drugs to standard therapy in the first-line treatment of ovarian cancer.

Advanced-stage epithelial ovarian cancer is generally managed with cytoreductive surgery and chemotherapy consisting of carboplatin and paclitaxel, achieving clinical complete remission in the majority of patients. However, most tumors recur, and are associated with progressive chemotherapy resistance. Techniques to optimize chemotherapy have included intraperitoneal administration and weekly scheduling of paclitaxel. Efforts to improve on the long-term results of primary therapy through addition of a third cytotoxic agent have not been successful, including extended maintenance, as well as strategies to overcome chemotherapy resistance. Limited data emerging from phase III trials using bevacizumab suggest some advantage in progression-free survival, particularly in the maintenance setting, and further data are awaited. At present, primary therapy with carboplatin and paclitaxel remains a well-tolerated standard regimen, including the option of weekly paclitaxel dosing, intraperitoneal delivery and neoadjuvant therapy in selected patients. Emerging biological paradigms will hopefully contribute to individualized treatment options in the future.

First-line randomized trials: revisiting the Ptolemaic universe.

Epithelial ovarian cancer is initially a chemosensitive neoplasm, with overall response rates to systemic platinum-based therapy exceeding 80% in conjunction with cytoreductive surgery. However, long-term survival remains poor due to eventual tumor recurrence and emergence of drug resistance. While platinum (cisplatin or carboplatin) and taxanes remain at the core of primary treatment, there has been increased interest in the evaluation of doublet and triplet combinations with diverse cytotoxic agents, including docetaxel, topotecan, gemcitabine, and PEG-liposomal doxorubicin. This has been prompted by single-agent activity in the setting of recurrent platinum-resistant disease and encouraging data from nonrandomized phase I-II trials. As a result, beginning in 1998, the international cooperative groups collaborated on a series of phase III trials to improve long-term outcomes through the development of new platinum-based combinations. More than 10,000 women have been randomized on these trials, and preliminary data from several studies have been reported. Although final data are pending, there is not currently any evidence to recommend adopting a new two- or three-drug combination, and carboplatin with paclitaxel remains the standard regimen of choice. Rapid developments in molecular-targeted therapy are challenging our paradigm for future clinical trials, and our priorities need to be carefully considered.

Proceedings of a GOG workshop on intraperitoneal therapy for ovarian cancer.

Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on intraperitoneal therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.

Standard treatment in advanced ovarian cancer in 2005: the state of the art.

What are standards? The oncology community expends considerable effort to review the results from definitive treatment studies and define recommendations for future studies, as well as standards of care for the community and patients who are not participating in clinical trials. This is a thoughtful and well-intentioned process but subject to considerable bias due to limitations in the data and/or their interpretation. While ovarian cancer is highly responsive to platinum-based therapy after initial cytoreductive surgery, there is a substantial risk of recurrence, which is accompanied by the emergence of drug-resistant disease. Better treatments with improved long-term outcomes are needed. From this perspective, standards can help to provide a baseline for assessing gaps in our current knowledge and defining priorities for future clinical trials. While not an exhaustive review, this study will focus on key clinical concepts that are guiding ovarian cancer research and treatment.

Is there still a role for hormonal therapy?

Ovarian cancer arises from the specialized surface epithelium, which routinely expresses receptors for reproductive hormones and growth factors. However, as a group, ovarian tumors are less responsive to hormonal therapy than either breast or endometrial cancer. The complex factors that govern hormonal response and associated molecular interactions are under intensive investigation, with the generation of new hypotheses that merit clinical evaluation. As such, it is reasonable to consider a number of potential hormonal interventions related to the prevention and treatment of ovarian cancer.

Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic.

Gemcitabine (2'2'-difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2' position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane-associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross-links, thereby leading to a G1 block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800-1250 mg/m2. dFdC is generally well tolerated, with the most frequently occurring dose-limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum-resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14-22% and a median duration of response of 4.0-10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated.

Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel vs. cisplatin and paclitaxel (GOG 158) and an update on GOG0 182-ICON5.

Mature results from GOG158 have clearly established carboplatin and paclitaxel as an effective and well tolerated standard regimen, providing a basis for the reference arm in GOG0182-ICON5, an ongoing multiarmed phase III trial of the Gynecologic Cancer InterGroup (GCIG) evaluating the incorporation of newer cytotoxic agents. Results from GOG158 will be reviewed, including an analysis of second-look surgical outcomes, followed by an update on the current status of GOG0182-ICON5.

Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel versus cisplatin and paclitaxel (GOG158) and an update on GOG0182-ICON5.

Mature results from GOG158 have clearly established carboplatin and paclitaxel as an effective and well-tolerated standard regimen, providing a basis for the reference arm in GOG0182-ICON5, an ongoing multiarmed phase III trial of the Gynecologic Cancer InterGroup (GCIG) evaluating the incorporation of newer cytotoxic agents. Results from GOG158 will be reviewed, including an analysis of second-look surgical outcomes, followed by an update on the current status of GOG0182-ICON5.

Developmental chemotherapy in advanced ovarian cancer: incorporation of topoisomerase-I inhibitors and perspective of the Gynecologic Oncology Group.

Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapy remains a priority. In particular, several interesting chemotherapy agents have demonstrated activity individually in patients with recurrent EOC. Among these are gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have suggested an advantage for combinations of these agents with platinum, which has been attributed to inhibition of DNA synthetic pathways involved in the repair of platinum-DNA adducts. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxicity, prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) has conducted a series of phase I pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial (GOG-0182) that will compare these combinations against carboplatin-paclitaxel. The selection of candidate regimens for this trial illustrate the challenges of drug development in EOC.