Creating work environments where people of all genders in gynecologic oncology can thrive: An SGO evidence-based review.

Equality, equity, and parity in the workplace are necessary to optimize patient care across all aspects of medicine. Gender-based inequities remain an obstacle to quality of care, including within the now majority women subspecialty of gynecologic oncology. The results of the 2020 SGO State of the Society Survey prompted this evidence-based review. Evidence related to relevant aspects of the clinical care model by which women with malignancies are cared for is summarized. Recommendations are made that include ways to create work environments where all members of a gynecologic oncology clinical care team, regardless of gender, can thrive. These recommendations aim to improve equality and equity within the specialty and, in doing so, elevate the care that our patients receive.

Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. PATIENTS AND METHODS: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression. RESULTS: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension. CONCLUSIONS: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0111648.

The new classifications of ovarian, fallopian tube, and primary peritoneal cancer and their clinical implications.

The roles of histologic characterization and staging are to provide reproducible metrics for cancer classification with which to direct the most appropriate clinical care and to yield the most stable reliable system to allow both prospective and retrospective data analysis. Both the histologic and staging classifications of malignant ovarian/tubal/peritoneal cancers have recently changed. The World Health Organization sponsored a review and reclassification of the pathology of cancers of the ovaries, fallopian tubes, and peritoneum, and published these updates in 2014. In so doing, they codified the two-tiered grading system that has been in use in serous ovarian cancers for nearly a decade. In parallel, FIGO reviewed and updated the surgical staging system, applied to all histotypes of ovarian, tubal, and peritoneal cancers, also published in 2014. In both cases, the changes made are meant to encompass a better understanding of disease, but both have important merits and drawbacks. Changes in staging complicate analysis of retrospective data against current data. Though in some aspects controversial, the changes overall are meant to represent a better biologic understanding of disease that we hope will lead to an improvement in patient care and directed therapy.

PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies.

Poly(ADP-ribose)polymerase inhibitors (PARPis) have shown promising activity in patients with BRCA1/2 mutation-associated (BRCA1/2(MUT+)) ovarian and breast cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of sporadic high-grade serous ovarian cancer, and cancers defective in DNA repair pathways, such as prostate, endometrial, and pancreatic cancers. Several PARPis are currently in phase 1/2 clinical investigation, with registration trials now being designed. Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2(MUT+) and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers. Understanding more about the molecular abnormalities involved in BRCA-like tumors, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers, is critical to rapidly advancing the field of PARPi therapy and improve clinical outcomes.

Clinical implications of using molecular diagnostics for ovarian cancers.

In the era of morphologic diagnostics, any epithelial tumor on or involving the ovaries was presumed to come from and be strictly of ovarian origin, apart from the rare but clearly metastatic tumors. Thus, many women who might have had small fallopian tube primary cancers that rapidly extended on to or into the ovary were deemed to have ovarian cancer. Now, as we begin to better understand that there are different types of cancers of nonuterine Muellerian origin, we expand upon the morphologic to add the molecular characteristics. Morphomolecular characteristics are being applied to drive clinical advances including development and optimization of predictive and prognostic biomarkers, redefinition of historical controls, and consideration of novel clinical trial designs. Ovarian cancer, not a common cancer to start with, is now subdivided into types, making ever smaller clinical cohorts. The first studies evaluating tubo-ovarian Muellerian cancers of morphomolecular types have begun. Deleterious mutations in BRCA1 or 2 have been validated as the first new predictive and prognostic biomarker of the high-grade serous ovarian cancer type and polyADPribose polymerase inhibitors, the first targeted agents for this morphomolecular entity. Similar progress is developing in other tubo-ovarian cancer types. This new knowledge is driving the building of a structure-function-type relationship that is generating novel clinically applicable hypotheses for testing.

Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions.

BACKGROUND: We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs). METHODS: Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered. RESULTS: All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6-65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR. CONCLUSION: Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.

Proteomics as a guiding tool for more effective personalized therapy.

Ovarian cancer remains the deadliest gynecological malignancy in the Western world and is most often diagnosed at a rarely curable late stage. Examination of protein end points has been employed as an investigative mechanism to guide targeted therapy and to stratify ovarian cancer. Proteomics allows characterization of the proteins and the associated protein and peptide modifications. This has given us insight into the perturbations of signaling pathways within tumor cells and has improved the discovery of new drug targets and possible prognostic indicators of outcome and disease response to therapy. Development of validated assays that survey the genetic and/or proteomic make-up of an individual tumor will add greatly to the histological classification of the tumor and may lead to different treatment approaches tailored to the unique expression pattern of each individual patient. It is anticipated that application of proteomics may bring to reality the clinical adoption of molecular stratification, e.g. not, 'is the gene overexpressed?', but 'is the pathway upregulated?' This will be successful if validated peptide biomarkers are applied for patient selection prospectively and with inclusion of preplanned biological correlates. These events will guide future directions of proteomics as a selector and as a validator and will guide how we integrate proteomics information daily into patient care and into selecting therapy of advanced and recurrent ovarian cancer and other cancers.

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.

BACKGROUND: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing. METHODS: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed. RESULTS: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation > or =4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months. CONCLUSION: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

Ovarian cancer in the proteomics era.

Ovarian cancer presents a diagnostic challenge because of its subtle clinical presentation and elusive cell of origin. Two new technologies of proteomics have advanced the dissection of the underlying molecular signaling events and the proteomic characterization of ovarian cancer: mass spectrometry and protein array analysis. Mass spectrometry can provide a snapshot of a proteome in time and space, with sensitivity and resolution that may allow identification of the elusive "needle in the haystack" heralding ovarian cancer. Proteomic profiling of tumor tissue samples can survey molecular targets during treatment and quantify changes using reverse phase protein arrays generated from tumor samples captured by microdissection, lysed and spotted in serial dilutions for high-throughput analysis. This approach can be applied to identify the optimal biological dose of a targeted agent and to validate target to outcome link. The evolution of proteomic technologies has the capacity to advance rapidly our understanding of ovarian cancer at a molecular level and thus elucidate new directions for the treatment of this disease.

Ovarian cancer in the proteomics era: diagnosis, prognosis, and therapeutics targets.

Ovarian cancer is clinically quiet as it plants seeds of metastases in the peritoneal cavity, even during early stages when there is highest potential for cure. The only available biomarker is CA125, which has an unacceptably low sensitivity and specificity for diagnostic use. Highly sensitive and specific tools to further optimize early diagnosis and treatment are needed. We propose that proteomic technologies have an important role to play in the development of these tools. Mass spectrometry platforms, such as surface-enhanced laser desorption/ionization time-of-flight, may be used to mine patient's serum for proteomic signatures that are shed by tumor and stroma. Such signatures could serve as a diagnostic tool during early-stage disease and as a remission-monitoring tool in later-stage disease. Reverse-phase protein microarrays are a new microproteomic tool to profile signaling pathways in ovarian cancer, thus identifying therapeutic targets while simultaneously suggesting prognostic indicators. Proteomic technologies have the capacity to build upon our genomic and clinical understanding of ovarian cancer by moving the focal point to the tumor and its microenvironment. This unique proteomic vantage point allows the creation of tools that will aid clinicians in making rational decisions in the diagnosis and treatment of women with ovarian cancer.

Malignant effusions are sources of fibronectin and other promigratory and proinvasive components.

Metastatic dissemination is the primary cause of death in ovarian cancer (OvCa) patients, and dissemination to pleural and peritoneal effusions is a common clinical event. Effusion samples were collected from 15 OvCa patients. Twenty-six samples were collected prospectively, two were archival, and eight were taken from patients with other malignancies. Twenty-nine samples were from malignant ascites, and seven specimens were pleural fluids. In addition, six ascites and two pleural fluids from noncancer patients were studied as effusion controls. Effusion supernatants were tested for migration-stimulation activity, using A2058 human melanoma cells as the index responder cell. Malignant samples induced a 400-1200% increase in migration. Sixty percent of the migration was inhibited by incubation of the malignant fluid with antifibronectin (FN) antibody, in contrast to 75% inhibition of control fluid-stimulated migration (P = 0.017). Gelatin zymography and Western blot analyses showed that latent and activated MMP-2 and MMP-9 collagenases, and tissue inhibitor of metalloproteinase-2 (TIMP-2) were present in all malignant fluids. Serial samples were taken from several patients, and a trend for correlation between MMPs and clinical behavior of the tumors was shown. Free TIMP-2 correlated with CA-125 levels in two patients for whom serial samples were available. The demonstration of promigratory and proinvasive activity in malignant effusions is consistent with their association with other metastatic disease in OvCa patients and their function as a haven for metastatic cells.

Proteomic analysis for the early detection and rational treatment of cancer--realistic hope?

Proteomics is an emerging field in medical science focused on the library of proteins specific to a given biosystem, the proteome, and understanding relationships therein. This field incorporates technologies that can be applied to serum and tissue in order to extract important biological information to aid clinicians and scientists in understanding the dynamic biology of their system of interest, such as a patient with cancer. These tools include laser capture microdissection, tissue lysate arrays and mass spectrometry approaches. These new technologies are more potent coupled with advanced bioinformatics analysis. They are used to characterize the content of, and changes in, the proteome induced by physiological changes, benign and pathologic. The application of these tools has assisted in the discovery of new biomarkers and may lead to new diagnostic tests and improvements in therapeutics. These tools additionally can provide a molecular characterization of cancers, which may allow for individualized molecular therapy. Understanding the basic concepts and tools used will illustrate how best to apply these technologies for patient benefit for the early detection of cancer and improved patient care.

High-resolution serum proteomic features for ovarian cancer detection.

Serum proteomic pattern diagnostics is an emerging paradigm employing low-resolution mass spectrometry (MS) to generate a set of biomarker classifiers. In the present study, we utilized a well-controlled ovarian cancer serum study set to compare the sensitivity and specificity of serum proteomic diagnostic patterns acquired using a high-resolution versus a low-resolution MS platform. In blinded testing sets, the high-resolution mass spectral data contained multiple diagnostic signatures that were superior to the low-resolution spectra in terms of sensitivity and specificity (P<0.00001) throughout the range of modeling conditions. Four mass spectral feature set patterns acquired from data obtained exclusively with the high-resolution mass spectrometer were 100% specific and sensitive in their diagnosis of serum samples as being acquired from either unaffected patients or those suffering from ovarian cancer. Important to the future of proteomic pattern diagnostics is the ability to recognize inferior spectra statistically, so that those resulting from a specific process error are recognized prior to their potentially incorrect (and damaging) diagnosis. To meet this need, we have developed a series of quality-assurance and in-process control procedures to (a) globally evaluate sources of sample variability, (b) identify outlying mass spectra, and (c) develop quality-control release specifications. From these quality-assurance and control (QA/QC) specifications, we identified 32 mass spectra out of the total 248 that showed statistically significant differences from the norm. Hence, 216 of the initial 248 high-resolution mass spectra were determined to be of high quality and were remodeled by pattern-recognition analysis. Again, we obtained four mass spectral feature set patterns that also exhibited 100% sensitivity and specificity in blinded validation tests (68/68 cancer: including 18/18 stage I, and 43/43 healthy). We conclude that (a) the use of high-resolution MS yields superior classification patterns as compared with those obtained with lower resolution instrumentation; (b) although the process error that we discovered did not have a deleterious impact on the present results obtained from proteomic pattern analysis, the major source of spectral variability emanated from mass spectral acquisition, and not bias at the clinical collection site; (c) this variability can be reduced and monitored through the use of QA/QC statistical procedures; (d) multiple and distinct proteomic patterns, comprising low molecular weight biomarkers, detected by high-resolution MS achieve accuracies surpassing individual biomarkers, warranting validation in a large clinical study.

Proteomic analysis for early detection of ovarian cancer: a realistic approach?

Ovarian cancer is a multifaceted disease wherein most women are diagnosed with advanced stage disease. One of the most imperative issues in ovarian cancer is early detection. Biomarkers that allow cancer detection at stage I, a time when the disease is amenable to surgical and chemotherapeutic cure in over 90% of patients, can dramatically alter the horizon for women with this disease. Recent developments in mass spectroscopy and protein chip technology coupled with bioinformatics have been applied to biomarker discovery. The complexity of the proteome is a rich resource from which the patterns can be gleaned; the pattern rather than its component parts is the diagnostic. Serum is a key source of putative protein biomarkers, and, by its nature, can reflect organ-confined events. Pioneering use of mass spectroscopy coupled with bioinformatics has been demonstrated as being capable of distinguishing serum protein pattern signatures of ovarian cancer in patients with early- and late-stage disease. This is a sensitive, precise, and promising tool for which further validation is needed to confirm that ovarian cancer serum protein signature patterns can be a robust biomarker approach for ovarian cancer diagnosis, yielding improved patient outcome and reducing the death and suffering from ovarian cancer.

Role of calcium in E-selectin induced phenotype of T84 colon carcinoma cells.

The adhesion of cancer cells to the endothelium during the metastatic process involves the interaction of specific cell-cell adhesion receptors on the cell surface. E-selectin on endothelial cells and sialyl Lewis X carbohydrate component on tumor cells are mainly implicated in the adhesion of colon carcinoma cells to the endothelium of target organ. In this paper we show that binding of E-selectin to T84 colon tumor cells causes approximately a twofold increase in intracellular calcium concentration. In particular, using two inhibitors of receptor operated calcium channels, CAI and SK&F 96365, we present evidences that the augmentation in cytoplasmic calcium originates from ionic influx from extracellular sources. Furthermore, we demonstrated that modulation of [Ca2+]i by engagement of E-selectin receptor starts signal transduction pathways that affect cell spreading, tyrosine phosphorylation signaling, and cancer cell motility.

Promising directions for the diagnosis and management of gynecological cancers.

Diagnosis and management of cancer requires tools with both high sensitivity and specificity. The minimally invasive cervical smear has demonstrated how a test, even one with low specificity, can change the public health profile of a cancer from a late stage deadly disease to early diagnosis with rare tumor-related deaths. The benefit of such a test is best demonstrated by the low frequency of cervix cancer and its good outcome in countries where this test is readily available and used with appropriate secondary follow up. Early and specific symptoms, and identification and prevention for high risk groups has had similar impact for endometrial cancer. Neither a robust test, nor reliable or specific early symptoms are available for ovarian cancer, making clinical and scientific advances in this area a critical world-wide need. Current approaches testing one protein or gene marker at a time will not address this crisis expeditiously. New sensitive, specific, accurate, and reliable technologies that can be implemented using high throughput mechanisms are needed at as low a cost as possible. Ideally, these technologies should be focused on readily available patient resources, such as blood or urine, or as in the case of cervix cancer, minimally invasive informative approaches such as cervical smears. Techniques that allow data mining from a large input database overcome the slow advances of one protein-one gene investigation, and further address the multi-faceted carcinogenesis process occurring even in germ line mutation-associated malignancy. Proteomics, the study of the cellular proteins and their activation states, has led the progress in biomarker development for ovarian and other cancers and is being applied to management assessment. Amenable to high throughput, internet interface, and representative of the proteome spectrum, proteomic technology is the newest and most promising direction for translational developments in gynecologic cancers.

Microarray gene expression profiling of angiogenesis inhibitors using the rat aortic ring assay.

The rat aortic ring assay has been previously described as a useful ex vivo model for analyzing the biological activity of various inhibitors of angiogenesis. Rat aortic rings are exposed to antiangiogenic agents for a five-day incubation period. Then, the degree of microvessel outgrowth from the rings is analyzed and quantified. In contrast to most in vitro angiogenesis assays, the rat aortic ring model provides a unique microenvironment to evaluate the interaction of various cell types and biological factors for their influence on angiogenesis. Microarray analysis is an accepted method for the evaluation of gene expression profiles and can be used to better understand changes in gene expression that occur when rat aortic rings are exposed to a particular biological agent. Here we describe a method of using microarray technology to evaluate the modulation of gene expression in angiogenesis using the rat aortic ring assay.

E-selectin modulates the malignant properties of T84 colon carcinoma cells.

The extravasation of metastatic cells is regulated by molecular events involving the initial adhesion of tumor cells to the endothelium and subsequently the migration of cells in the host connective tissue. E-selectin on endothelial cells and sialyl Lewis X carbohydrate component on tumor cells are mainly involved in the adhesion of colon carcinoma cells to the endothelium of target organ. Interaction of T84 colon cancer cells to purified E-selectin in vitro caused an increase in the tyrosine phosphorylation of a number of proteins as well as the modulation of cellular properties correlated to the metastatic phenotype. Specifically, E-selectin-stimulated actin reorganization, increased collagenase secretion, and induced cell migration. Treatment of T84 cells with herbimycin A inhibited cell adhesion as well as selectin-induced increase of cell migration, and cytoskeleton assembly. Our data demonstrate that binding of cancer cells to E-selectin starts signal transduction pathways which may affect the tumor metastatic abilities.