O'Driscoll M
Diseases associated with defective responses to DNA damage.
Cold Spring Harb Perspect Biol. 2012; 4(12) [PubMed]

Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.

Human DNA Damage Response Disorders Group Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RQ

Mukhopadhyay A, Plummer ER, Elattar A, et al.
Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: sensitivity to PARP inhibitors, platinum, and survival.
Cancer Res. 2012; 72(22):5675-82 [PubMed]

Up to 50% of epithelial ovarian cancers (EOC) display defects in the homologous recombination (HR) pathway. We sought to determine the ramifications of the homologous recombination-deficient (HRD) status on the clinicopathologic features, chemotherapy response, and survival outcomes of patients with EOCs. HR status was determined in primary cultures from ascitic fluid in 50 chemotherapy-naïve patients by a functional RAD51 immunofluorescence assay and correlated with in vitro sensitivity to the PARP inhibitor (PARPi), rucaparib. All patients went on to receive platinum-based chemotherapy; platinum sensitivity, tumor progression, and overall survival were compared prospectively in HR-competent versus HRD patients. Compared with HR-competent patients, the HRD group was predominantly serous with a higher median CA125 at presentation. HRD was associated with higher ex vivo PARPi sensitivity and clinical platinum sensitivity. Median follow-up duration was 14 months; patients in the HRD group had lower tumor progression rates at 6 months, lower overall/disease-specific death rates at 12 months, and higher median survival. We therefore suggest that HRD as predicted by a functional RAD51 assay correlates with in vitro PARPi sensitivity, clinical platinum sensitivity, and improved survival outcome.

Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, N Ireland

Kaye SB, Fehrenbacher L, Holloway R, et al.
A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission.
Clin Cancer Res. 2012; 18(23):6509-18 [PubMed]

PURPOSE: Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor-stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR).
EXPERIMENTAL DESIGN: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).
RESULTS: One hundred four patients were randomized to vismodegib (n = 52) or placebo (n = 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.46-1.35]. The HR was 0.66 (95% CI, 0.36-1.20) for second CR patients (n = 84) and 1.79 (95% CI, 0.50-6.48) for third CR patients (n = 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues.
CONCLUSIONS: In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected.

Royal Marsden Hospital, Sutton, Surrey

Galazis N, Olaleye O, Haoula Z, et al.
Proteomic biomarkers for ovarian cancer risk in women with polycystic ovary syndrome: a systematic review and biomarker database integration.
Fertil Steril. 2012; 98(6):1590-601.e1 [PubMed]

OBJECTIVE: To review and identify possible biomarkers for ovarian cancer (OC) in women with polycystic ovary syndrome (PCOS).
DESIGN: Systematic literature searches of MEDLINE, EMBASE, and Cochrane using the search terms "proteomics," "proteomic," and "ovarian cancer" or "ovarian carcinoma." Proteomic biomarkers for OC were then integrated with an updated previously published database of all proteomic biomarkers identified to date in patients with PCOS.
SETTING: Academic department of obstetrics and gynecology in the United Kingdom.
PATIENT(S): A total of 180 women identified in the six studies.
INTERVENTION(S): Tissue samples from women with OC vs. tissue samples from women without OC.
MAIN OUTCOME MEASURE(S): Proteomic biomarkers, proteomic technique used, and methodologic quality score.
RESULT(S): A panel of six biomarkers was overexpressed both in women with OC and in women with PCOS. These biomarkers include calreticulin, fibrinogen-γ, superoxide dismutase, vimentin, malate dehydrogenase, and lamin B2.
CONCLUSION(S): These biomarkers could help improve our understanding of the links between PCOS and OC and could potentially be used to identify subgroups of women with PCOS at increased risk of OC. More studies are required to further evaluate the role these biomarkers play in women with PCOS and OC.

Division of Human Development, School of Clinical Sciences, University of Nottingham, Queen's Medical Centre Campus, Nottingham University Hospitals, Nottingham

Ferreras C, Rushton G, Cole CL, et al.
Endothelial heparan sulfate 6-O-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor.
J Biol Chem. 2012; 287(43):36132-46 [PubMed] Article available free on PMC after 19/10/2013

Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor 165 (VEGF(165)) are potent pro-angiogenic growth factors that play a pivotal role in tumor angiogenesis. The activity of these growth factors is regulated by heparan sulfate (HS), which is essential for the formation of FGF2/FGF receptor (FGFR) and VEGF(165)/VEGF receptor signaling complexes. However, the structural characteristics of HS that determine activation or inhibition of such complexes are only partially defined. Here we show that ovarian tumor endothelium displays high levels of HS sequences that harbor glucosamine 6-O-sulfates when compared with normal ovarian vasculature where these sequences are also detected in perivascular area. Reduced HS 6-O-sulfotransferase 1 (HS6ST-1) or 6-O-sulfotransferase 2 (HS6ST-2) expression in endothelial cells impacts upon the prevalence of HS 6-O-sulfate moieties in HS sequences, which consist of repeating short, highly sulfated S domains interspersed by transitional N-acetylated/N-sulfated domains. 1-40% reduction in 6-O-sulfates significantly compromises FGF2- and VEGF(165)-induced endothelial cell sprouting and tube formation in vitro and FGF2-dependent angiogenesis in vivo. Moreover, HS on wild-type neighboring endothelial or smooth muscle cells fails to restore endothelial cell sprouting and tube formation. The affinity of FGF2 for HS with reduced 6-O-sulfation is preserved, although FGFR1 activation is inhibited correlating with reduced receptor internalization. These data show that 6-O-sulfate moieties in endothelial HS are of major importance in regulating FGF2- and VEGF(165)-dependent endothelial cell functions in vitro and in vivo and highlight HS6ST-1 and HS6ST-2 as potential targets of novel antiangiogenic agents.

Translational Angiogenesis Group, School of Cancer and Enabling Sciences, The University of Manchester, Manchester M20 4BX

Richards FM, Tape CJ, Jodrell DI, Murphy G
Anti-tumour effects of a specific anti-ADAM17 antibody in an ovarian cancer model in vivo.
PLoS One. 2012; 7(7):e40597 [PubMed] Article available free on PMC after 19/10/2013

ADAM 17 (TNF-α converting enzyme, TACE) is a potential target for cancer therapy, but the small molecule inhibitors reported to date are not specific to this ADAM family member. This membrane-bound metalloproteinase is responsible for ectodomain shedding of pathologically significant substrates including TNF-α and EGFR ligands. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics and anti-tumour efficacy of the first specific inhibitor, an anti-human ADAM17 IgG antibody, clone D1(A12). We used intraperitoneal xenografts of the human ovarian cancer cell line IGROV1-Luc in Balb/c nude mice, chosen because it was previously reported that growth of these xenografts is inhibited by knock-down of TNF-α. In vitro, 200 nM D1(A12) inhibited shedding of ADAM17 substrates TNF-α, TNFR1-α, TGF-α, amphiregulin (AREG), HB-EGF and IL-6Rα, from IGROV1-Luc cells, (4.7 nM IC(50) for TNF-α shedding). In IGROV1-Luc xenografts in vivo, D1(A12) IgG showed pharmacokinetic properties suitable for efficacy studies, with a single i.p. dose of 10 mg/kg D1(A12) sufficient to maintain IgG plasma and ascites fluid concentrations above 100 nM for more than 7 days. The plasma half life was 8.6 days. Next, an efficacy study was performed, dosing D1(A12) or anti-human TNF-α antibody infliximab at 10 mg/kg q7d, quantifying IGROV1-Luc tumour burden by bioluminescence. D1(A12) IgG showed a significant reduction in tumour growth (p = 0.005), 56% of vehicle control. Surprisingly, D1(A12) did not reduce the concentration of circulating human TNF-α, suggesting that another enzyme may compensate for inhibition of ADAM17 in vivo (but not in vitro). However, D1(A12) did show clear pharmacodynamic effects in the mice, with significant inhibition of shedding from tumour of ADAM17 substrates TNFR1-α, AREG, and TGF-α (4-15-fold reductions, p<0.0001 for all three). Thus, D1(A12) has anti-ADAM17 activity in vivo, inhibits shedding of EGFR ligands and has potential for use in EGF ligand-dependent tumours.

Pharmacology & Drug Development Group, Cancer Research UK Cambridge Research Institute, and Department of Oncology, University of Cambridge, Cambridge

Brüning-Richardson A, Bond J, Alsiary R, et al.
NuMA overexpression in epithelial ovarian cancer.
PLoS One. 2012; 7(6):e38945 [PubMed] Article available free on PMC after 19/10/2013

Highly aneuploid tumours are common in epithelial ovarian cancers (EOC). We investigated whether NuMA expression was associated with this phenomenon.NuMA protein levels in normal and tumour tissues, ovarian cell lines and primary cultures of malignant cells derived from ovarian ascitic fluids were analysed by Affymetrix microarray analysis, immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF), with results correlated to associated clinical data. Aneuploidy status in primary cultures was determined by FACS analysis.Affymetrix microarray data indicated that NuMA was overexpressed in tumour tissue, primary cultures and cell lines compared to normal ovarian tissue. IHC revealed low to weak NuMA expression in normal tissues. Expression was upregulated in tumours, with a significant association with disease stage in mucinous EOC subtypes (p = 0.009), lymph node involvement (p = 0.03) and patient age (p = 0.04). Additional discontinuous data analysis revealed that high NuMA levels in tumours decreased with grade (p = 0.02) but increased with disease stage (p = 0.04) in serous EOC. NuMA expression decreased in late disease stage 4 endometrioid EOCs. High NuMA levels decreased with increased tumour invasion in all subtypes (p = 0.03). IF of primary cultures revealed that high NuMA levels at mitotic spindle poles were significantly associated with a decreased proportion of cells in cytokinesis (p = 0.05), increased binucleation (p = 0.021) and multinucleation (p = 0.007), and aneuploidy (p = 0.008).NuMA is highly expressed in EOC tumours and high NuMA levels correlate with increases in mitotic defects and aneuploidy in primary cultures.

Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds

Barnes DR, Lee A,
Evaluation of association methods for analysing modifiers of disease risk in carriers of high-risk mutations.
Genet Epidemiol. 2012; 36(3):274-91 [PubMed]

There is considerable evidence indicating that disease risk in carriers of high-risk mutations (e.g. BRCA1 and BRCA2) varies by other genetic factors. Such mutations tend to be rare in the population and studies of genetic modifiers of risk have focused on sampling mutation carriers through clinical genetics centres. Genetic testing targets affected individuals from high-risk families, making ascertainment of mutation carriers non-random with respect to disease phenotype. Standard analytical methods can lead to biased estimates of associations. Methods proposed to address this problem include a weighted-cohort (WC) and retrospective likelihood (RL) approach. Their performance has not been evaluated systematically. We evaluate these methods by simulation and extend the RL to analysing associations of two diseases simultaneously (competing risks RL-CRRL). The standard cohort approach (Cox regression) yielded the most biased risk ratio (RR) estimates (relative bias-RB: -25% to -17%) and had the lowest power. The WC and RL approaches provided similar RR estimates, were least biased (RB: -2.6% to 2.5%), and had the lowest mean-squared errors. The RL method generally had more power than WC. When analysing associations with two diseases, ignoring a potential association with one disease leads to inflated type I errors for inferences with respect to the second disease and biased RR estimates. The CRRL generally gave unbiased RR estimates for both disease risks and had correct nominal type I errors. These methods are illustrated by analyses of genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.

Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge

Balogun N, Forbes A, Widschwendter M, Lanceley A
Noninvasive nutritional management of ovarian cancer patients: beyond intestinal obstruction.
Int J Gynecol Cancer. 2012; 22(6):1089-95 [PubMed]

OBJECTIVE: Malnutrition, suffered by more than 50% of patients with ovarian cancer during the course of their disease, significantly compromises the effectiveness of treatment, causes distress, and increases morbidity and mortality. This review outlines the nutritional challenges faced by women with ovarian cancer and evaluates the evidence base for current practice and possible opportunities for intervention in clinical settings.
METHODS: PubMed and MetaLib databases were searched for literature on nutrition and cancer/ovarian cancer using terms and truncations covering cancer, cachexia, mouse models, malnutrition, and nutrition intervention. MEDLINE and Cochrane databases were separately searched for interventional studies and clinical and randomized controlled trials published in English (UK/United States) that involved oral nutrition and/or supplementation/intervention in ovarian cancer patients.
RESULTS: Malnutrition continues to be a significant challenge in ovarian cancer management despite significant improvement in treatment pathways and understanding of metabolic pathways and the role of inflammation. There is little evidence of studies designed to evaluate the impact of additional oral nutrients in this population. Seven studies found compared "early" versus "traditional" postoperative oral feeding after major gynecological/oncological surgery, and 1 study evaluated the impact of nutritional status on survival. The 7 studies found evidence of safety, tolerability, reduction in length of hospitalization, and rapid recovery after early feeding. There is no evidence of benefit of additional oral nutrients in this population.
CONCLUSIONS: Current guidelines and protocols of nutritional management of ovarian cancer seem to be based on expert opinion. There is need for extensive collaborative evidence for nutritional management decisions made in the treatment of patients. Prospective cohort studies could help evaluate the impact of changes in nutritional status on health/nutritional outcomes, disease recurrence, quality of life, and survival. These would form a basis for well-designed, targeted, randomized controlled trials with specific and controlled nutrients/counseling aimed at preventing rather than treating nutritional complications.

Department of Women's Cancer, EGA Institute for Women's Health, University College London, London

Tumbarello DA, Temple J, Brenton JD
ß3 integrin modulates transforming growth factor beta induced (TGFBI) function and paclitaxel response in ovarian cancer cells.
Mol Cancer. 2012; 11:36 [PubMed] Article available free on PMC after 19/10/2013

BACKGROUND: The extracellular matrix (ECM) has a key role in facilitating the progression of ovarian cancer and we have shown recently that the secreted ECM protein TGFBI modulates the response of ovarian cancer to paclitaxel-induced cell death.
RESULTS: We have determined TGFBI signaling from the extracellular environment is preferential for the cell surface αvß3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a ß1 integrin-mediated pathway. We demonstrate that suppression of ß1 integrin expression, in ß3 integrin-expressing ovarian cancer cells, increases adhesion to rTGFBI. In addition, Syndecan-1 and -4 expression is dispensable for adhesion to rTGFBI and loss of Syndecan-1 cooperates with the loss of ß1 integrin to further enhance adhesion to rTGFBI. The RGD motif present in the carboxy-terminus of TGFBI is necessary, but not sufficient, for SKOV3 cell adhesion and is dispensable for adhesion of ovarian cancer cells lacking ß3 integrin expression. In contrast to TGFBI, the carboxy-terminus of periostin, lacking a RGD motif, is unable to support adhesion of ovarian cancer cells. Suppression of ß3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of ß1 integrin has no effect. Furthermore, suppression of TGFBI expression stimulates a paclitaxel resistant phenotype while suppression of fibronectin expression, which primarily signals through a ß1 integrin-mediated pathway, increases paclitaxel sensitivity.
CONCLUSIONS: Therefore, different ECM components use distinct signaling mechanisms in ovarian cancer cells and in particular, TGFBI preferentially interacts through a ß3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.

Cancer Research UK, Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE

Melvin JC, Seth D, Holmberg L, et al.
Lipid profiles and risk of breast and ovarian cancer in the Swedish AMORIS study.
Cancer Epidemiol Biomarkers Prev. 2012; 21(8):1381-4 [PubMed]

BACKGROUND: Obesity is a risk factor for breast and ovarian cancer; the mechanisms of action are not completely understood. Perturbed lipid metabolism often accompanies obesity; we therefore ascertained the associations between lipid components and breast and ovarian cancer risk in a prospective cohort study.
METHODS: A total of 234,494 women with baseline measurements of triglycerides and total cholesterol and glucose were selected from the AMORIS database.A total of 27,394 had measurements of high-density lipoprotein, low-density lipoprotein, apolipoprotein (Apo) B, and A-I. Associations between quartiles and dichotomized values of lipid components and breast and ovarian cancer risk were analyzed using Cox proportional hazard models.
RESULTS: We identified 6,105 women diagnosed with breast cancer and 808 women diagnosed with ovarian cancer. A weak trend was observed between triglycerides and breast cancer (HR, 1.01, 95% Confidence Interval, 0.94-1.09; 0.93 (0.86-1.00) 0.91 (0.84-0.99), second, third, and fourth quartiles; P = 0.01). No other associations between lipid components and risk of breast cancer or ovarian cancer showed statistical significance.
CONCLUSIONS: A weak protective association was found between levels of triglycerides and risk of breast cancer.
IMPACT: An analysis including information on tumour characteristics of ovarian cancer and breast cancer may provide more insight in possible links between lipid metabolism and the risk of these cancers.

1King's College London, School of Medicine, Division of Cancer Studies, Cancer Epidemiology Group, London

McKie AB, Vaughan S, Zanini E, et al.
The OPCML tumor suppressor functions as a cell surface repressor-adaptor, negatively regulating receptor tyrosine kinases in epithelial ovarian cancer.
Cancer Discov. 2012; 2(2):156-71 [PubMed] Article available free on PMC after 19/10/2013

UNLABELLED: Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy, and its molecular basis is poorly understood. We previously demonstrated that opioid binding protein cell adhesion molecule (OPCML) was frequently epigenetically inactivated in epithelial ovarian cancers, with tumor suppressor function in vitro and in vivo. Here, we further show the clinical relevance of OPCML and demonstrate that OPCML functions by a novel mechanism in epithelial ovarian cancer cell lines and normal ovarian surface epithelial cells by regulating a specific repertoire of receptor tyrosine kinases: EPHA2, FGFR1, FGFR3, HER2, and HER4. OPCML negatively regulates receptor tyrosine kinases by binding their extracellular domains, altering trafficking via nonclathrin-dependent endocytosis, and promoting their degradation via a polyubiquitination-associated proteasomal mechanism leading to signaling and growth inhibition. Exogenous recombinant OPCML domain 1-3 protein inhibited the cell growth of epithelial ovarian cancers cell in vitro and in vivo in 2 murine ovarian cancer intraperitoneal models that used an identical mechanism. These findings demonstrate a novel mechanism of OPCML-mediated tumor suppression and provide a proof-of-concept for recombinant OPCML protein therapy in epithelial ovarian cancers.
SIGNIFICANCE: The OPCML tumor suppressor negatively regulates a specific spectrum of receptor tyrosine kinases in ovarian cancer cells by binding to their extracellular domain and altering trafficking to a nonclathrin, caveolin-1–associated endosomal pathway that results in receptor tyrosine kinase polyubiquitination and proteasomal degradation. Recombinant OPCML domain 1-3 recapitulates this mechanism and may allow for the implementation of an extracellular tumor-suppressor replacement strategy.

Ovarian Cancer Action Research Centre, Division of Cancer, Imperial College London Hammersmith Campus, London

Carden CP, Stewart A, Thavasu P, et al.
The association of PI3 kinase signaling and chemoresistance in advanced ovarian cancer.
Mol Cancer Ther. 2012; 11(7):1609-17 [PubMed]

Evidence that the phosphoinositide 3-kinase (PI3K) pathway is deregulated in ovarian cancer is largely based on the analysis of surgical specimens sampled at diagnosis and may not reflect the biology of advanced ovarian cancer. We aimed to investigate PI3K signaling in cancer cells isolated from patients with advanced ovarian cancer. Ascites samples were analyzed from 88 patients, of whom 61 received further treatment. Cancer cells were immunomagnetically separated from ascites, and the signaling output of the PI3K pathway was studied by quantifying p-AKT, p-p70S6K, and p-GSK3β by ELISA. Relevant oncogenes, such as PIK3CA and AKT, were sequenced by PCR-amplified mass spectroscopy detection methods. In addition, PIK3CA and AKT2 amplifications and PTEN deletions were analyzed by FISH. p-p70S6K levels were significantly higher in cells from 37 of 61 patients who did not respond to subsequent chemotherapy (0.7184 vs. 0.3496; P = 0.0100), and this difference was greater in patients who had not received previous chemotherapy. PIK3CA and AKT mutations were present in 5% and 0% of samples, respectively. Amplification of PIK3CA and AKT2 and deletion of PTEN was seen in 10%, 10%, and 27% of samples, respectively. Mutations of PIK3CA and amplification of PIK3CA/AKT2 or deletion of PTEN did not correlate with levels of p-AKT, p-p70S6K, and p-GSK3β. In patients with advanced ovarian cancer, there is an association between levels of p-p70S6K and response to subsequent chemotherapy. There is no clear evidence that this is driven specifically by PIK3CA or AKT mutations or by amplifications or deletion of PTEN.

Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutic, The Institute of Cancer Research, Sutton,United Kingdom.

Ledermann J, Harter P, Gourley C, et al.
Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
N Engl J Med. 2012; 366(15):1382-92 [PubMed]

BACKGROUND: Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations.
METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines.
RESULTS: Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75).
CONCLUSIONS: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

University College London (UCL) Cancer Institute, UCL & UCL Hospitals Comprehensive Biomedical Research Centre, 90 Tottenham Court Rd., London W1T 4TJ

Saha A, Varughese M, Gallagher CJ, et al.
Primary chemotherapy for inoperable ovarian, fallopian tube, or primary peritoneal cancer with or without delayed debulking surgery.
Int J Gynecol Cancer. 2012; 22(4):566-72 [PubMed]

OBJECTIVE: To describe the outcome of primary chemotherapy for women with advanced-stage epithelial ovarian or primary peritoneal cancer and delayed surgery when optimal debulking surgery cannot be achieved at diagnosis.
METHODS: Between 1998 and 2006, we retrospectively reviewed the overall survival and examined prognostic markers in consecutive patients who were not suitable for initial radical surgery because of the extent of disease and/or poor performance status. They were treated with a policy of primary platinum-based chemotherapy, followed whenever possible in responding patients by debulking surgery.
RESULTS: A total of 171 patients received least one cycle of chemotherapy. Eighty-six patients proceeded to surgery and 53 (31% of 171 and 62% of 86) had optimal (<1 cm) residual disease. Eighty-five patients did not undergo surgery because they remained unfit or had not responded sufficiently to chemotherapy. The median overall survival was 18.7 months (95% confidence interval [CI], 16.5-24.2). The median OS in the surgical group for optimal and suboptimal surgery was 40.8 (95% CI, 32.5-50.0) and 22.5 (95% CI, 17.7-37.1) months (P = 0.005). On multivariate analysis, interval surgery and optimal surgery were the only independent prognostic factors (hazard ratios, 0.45 and 0.43, respectively; P = 0.009). In the nonsurgical group, CA125 response was an independent prognostic factor (hazard ratio, 0.34; P = 0.001) with an OS of 21.7 months (95% CI, 14.0-35.4) in women with a normal CA125 after treatment compared with 6.7 (95% CI, 4.5-7.8) months.
CONCLUSIONS: In one third of the women, the tumor was optimally debulked after primary chemotherapy and their median survival was 40.8 months. Suboptimal debulking surgery after primary chemotherapy did not result in a better survival than that achieved after a chemotherapy response alone, suggesting that surgery may be avoided when imaging after chemotherapy demonstrates residual disease that cannot be optimally debulked.

Department of Medical Oncology, St. Bartholomew's Hospital, London

Chen SS, Michael A, Butler-Manuel SA
Advances in the treatment of ovarian cancer: a potential role of antiinflammatory phytochemicals.
Discov Med. 2012; 13(68):7-17 [PubMed]

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies worldwide. The five-year survival rates for stage IIIC and IV patients are 29% and 13%, respectively. Type-2 EOC cells have been found to be associated with this late stage disease. In contrast, women diagnosed in stage 1 disease, which mostly exhibits type-1 cells, have a high 5-year survival rate (90%). Recent progress in understanding the pathogenesis of EOC and inflammatory signaling pathways revealed that type-2 cells frequently express a deleted or mutated TP53 (60-80%), or aberrations in BRCA1 (30-60%) and BRCA2 (15-30%). The deletion or mutation of TP53 results in a dysregulated inflammatory signal network and contributes to an immunosuppressive microenvironment. Thus, to be effective, EOC therapy may be necessary to cover two areas: (1) direct cytotoxic killing of cancer cells; (2) reversion of the immunosuppressive microenvironment. Presently the first strategy is advancing rapidly while the second strategy remains behind. Isolation and characterization of cancer stem cells (CSCs) have helped to confirm the dynamic role of the tumor microenvironment in promoting cancer metastasis and recurrence. Based on widely published in vitro and mouse-model data, some anti-inflammatory phytochemicals appear to exhibit activity in modulating the tumor microenvironment. Specifically, apiegenin, baicalein, curcumin, EGCG, genistein, luteolin, oridonin, quercetin, and wogonin repress NF-kappaB (NF-κB, a proinflammatory transcription factor) and inhibit proinflammatory cytokines such as TNF-α and IL-6. Additionally, most of these phytochemicals have been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance. Recent studies further indicate that apigenin, genistein, kaempferol, luteolin, and quercetin potently inhibit VEGF production and suppress ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted.

Department of Research and Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey

Arora RS, Alston RD, Eden TO, et al.
Comparative incidence patterns and trends of gonadal and extragonadal germ cell tumors in England, 1979 to 2003.
Cancer. 2012; 118(17):4290-7 [PubMed]

BACKGROUND: It is believed that gonadal and extragonadal germ cell tumors (GCTs) arise from primordial germ cells and may have similar etiopathogenesis. Unlike testicular GCTs, there has been limited comprehensive population-based analysis of ovarian and extragonadal GCTs.
METHODS: All malignant GCTs and all central nervous system (CNS) GCTs with benign and uncertain behavior that were registered in England in the age group 0 to 84 years from 1979 to 2003 were included in the current study. Incidence rates were calculated and adjusted to the world standard population.
RESULTS: There were 33,364 GCTs (92.5% testes, 3.9% ovary, 3.2% extragonadal) in individuals aged 0 to 84 years. The CNS was the most common extragonadal site. An initial peak in incidence at ages 0 to 4 years of nongerminomas was observed at all sites except ovary. Second incidence peaks between ages 10 to 39 years that were more marked among males also were observed at all sites. The ages at these incidence peaks varied by site and were 10 to 14 years (CNS), 15 to 19 years (ovary), 25 to 29 years (other extragonadal sites), and 30 to 34 years (testes). A statistically significant increase in incidence over time was observed in germinomas (testes, CNS) and nongerminomas (testes, ovary).
CONCLUSIONS: The age-incidence patterns observed suggested a common initiation of GCTs in embryonic/fetal life with variable rates of tumor progression as a result of subsequent events that may be site specific. The authors concluded that future genetic studies should consider GCTs from all sites to enable a better understanding of their etiology.

Pediatric Oncology Department, Alder Hey Hospital, Liverpool

Perren TJ, Swart AM, Pfisterer J, et al.
A phase 3 trial of bevacizumab in ovarian cancer.
N Engl J Med. 2011; 365(26):2484-96 [PubMed]

BACKGROUND: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease.
METHODS: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival.
RESULTS: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months.
CONCLUSIONS: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

St. James's Institute of Oncology, St. James's University Hospital, Leeds

Mavaddat N, Barrowdale D, Andrulis IL, et al.
Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Cancer Epidemiol Biomarkers Prev. 2012; 21(1):134-47 [PubMed] Article available free on PMC after 19/10/2013

BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.
METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.
RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge

Dickinson RE, Fegan KS, Ren X, et al.
Glucocorticoid regulation of SLIT/ROBO tumour suppressor genes in the ovarian surface epithelium and ovarian cancer cells.
PLoS One. 2011; 6(11):e27792 [PubMed] Article available free on PMC after 19/10/2013

The three SLIT ligands and their four ROBO receptors have fundamental roles in mammalian development by promoting apoptosis and repulsing aberrant cell migration. SLITs and ROBOs have emerged as candidate tumour suppressor genes whose expression is inhibited in a variety of epithelial tumours. We demonstrated that their expression could be negatively regulated by cortisol in normal ovarian luteal cells. We hypothesised that after ovulation the locally produced cortisol would inhibit SLIT/ROBO expression in the ovarian surface epithelium (OSE) to facilitate its repair and that this regulatory pathway was still present, and could be manipulated, in ovarian epithelial cancer cells. Here we examined the expression and regulation of the SLIT/ROBO pathway in OSE, ovarian cancer epithelial cells and ovarian tumour cell lines. Basal SLIT2, SLIT3, ROBO1, ROBO2 and ROBO4 expression was lower in primary cultures of ovarian cancer epithelial cells when compared to normal OSE (P<0.05) and in poorly differentiated SKOV-3 cells compared to the more differentiated PEO-14 cells (P<0.05). Cortisol reduced the expression of certain SLITs and ROBOs in normal OSE and PEO-14 cells (P<0.05). Furthermore blocking SLIT/ROBO activity reduced apoptosis in both PEO-14 and SKOV-3 tumour cells (P<0.05). Interestingly SLIT/ROBO expression could be increased by reducing the expression of the glucocorticoid receptor using siRNA (P<0.05). Overall our findings indicate that in the post-ovulatory phase one role of cortisol may be to temporarily inhibit SLIT/ROBO expression to facilitate regeneration of the OSE. Therefore this pathway may be a target to develop strategies to manipulate the SLIT/ROBO system in ovarian cancer.

Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Edinburgh

Kulbe H, Chakravarty P, Leinster DA, et al.
A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment.
Cancer Res. 2012; 72(1):66-75 [PubMed] Article available free on PMC after 19/10/2013

Constitutive production of inflammatory cytokines is a characteristic of many human malignant cell lines; however, the in vitro and in vivo interdependence of these cytokines, and their significance to the human cancer microenvironment, are both poorly understood. Here, we describe for the first time how three key cytokine/chemokine mediators of cancer-related inflammation, TNF, CXCL12, and interleukin 6, are involved in an autocrine cytokine network, the "TNF network," in human ovarian cancer. We show that this network has paracrine actions on angiogenesis, infiltration of myeloid cells, and NOTCH signaling in both murine xenografts and human ovarian tumor biopsies. Neutralizing antibodies or siRNA to individual members of this TNF network reduced angiogenesis, myeloid cell infiltration, and experimental peritoneal ovarian tumor growth. The dependency of network genes on TNF was shown by their downregulation in tumor cells from patients with advanced ovarian cancer following the infusion of anti-TNF antibodies. Together, the findings define a network of inflammatory cytokine interactions that are crucial to tumor growth and validate this network as a key therapeutic target in ovarian cancer.

Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Cancer Research UK, Bioinformatics and Biostatistics Service, London

Goltsov A, Faratian D, Langdon SP, et al.
Features of the reversible sensitivity-resistance transition in PI3K/PTEN/AKT signalling network after HER2 inhibition.
Cell Signal. 2012; 24(2):493-504 [PubMed]

Systems biology approaches that combine experimental data and theoretical modelling to understand cellular signalling network dynamics offer a useful platform to investigate the mechanisms of resistance to drug interventions and to identify combination drug treatments. Extending our work on modelling the PI3K/PTEN/AKT signalling network (SN), we analyse the sensitivity of the SN output signal, phospho-AKT, to inhibition of HER2 receptor. We model typical aberrations in this SN identified in cancer development and drug resistance: loss of PTEN activity, PI3K and AKT mutations, HER2 overexpression, and overproduction of GSK3β and CK2 kinases controlling PTEN phosphorylation. We show that HER2 inhibition by the monoclonal antibody pertuzumab increases SN sensitivity, both to external signals and to changes in kinetic parameters of the proteins and their expression levels induced by mutations in the SN. This increase in sensitivity arises from the transition of SN functioning from saturation to non-saturation mode in response to HER2 inhibition. PTEN loss or PIK3CA mutation causes resistance to anti-HER2 inhibitor and leads to the restoration of saturation mode in SN functioning with a consequent decrease in SN sensitivity. We suggest that a drug-induced increase in SN sensitivity to internal perturbations, and specifically mutations, causes SN fragility. In particular, the SN is vulnerable to mutations that compensate for drug action and this may result in a sensitivity-to-resistance transition. The combination of HER2 and PI3K inhibition does not sensitise the SN to internal perturbations (mutations) in the PI3K/PTEN/AKT pathway: this combination treatment provides both synergetic inhibition and may prevent the SN from acquired mutations causing drug resistance. Through combination inhibition treatments, we studied the impact of upstream and downstream interventions to suppress resistance to the HER2 inhibitor in the SN with PTEN loss. Comparison of experimental results of PI3K inhibition in the PTEN upstream pathway with PDK1 inhibition in the PTEN downstream pathway shows that upstream inhibition abrogates resistance to pertuzumab more effectively than downstream inhibition. This difference in inhibition effect arises from the compensatory mechanism of an activation loop induced in the downstream pathway by PTEN loss. We highlight that drug target identification for combination anti-cancer therapy needs to account for the mutation effects on the upstream and downstream pathways.

Centre for Research in Informatics and Systems Pathology (CRISP), University of Abertay Dundee, Dundee

Banerjee S, Kaye S
The role of targeted therapy in ovarian cancer.
Eur J Cancer. 2011; 47 Suppl 3:S116-30 [PubMed]

Ovarian cancer is the second most common gynaecological malignancy and the leading cause of death from gynaecological cancer. Although in some cases treatment is initially effective, there is a considerable risk of disease recurrence and resistance to therapy. Therapies targeting molecular alterations in tumours offer the promise of significantly improved treatment. So far, the most promising targeted agents are angiogenesis inhibitors and PARP inhibitors. Here, we review the various targeted therapeutic approaches under clinical investigation in phase I and II trials of ovarian cancer and the challenges facing their future success in the clinic.

The Royal Marsden NHS Foundation Trust, Sutton, Surrey

Ledermann JA, Raja FA
Clinical trials and decision-making strategies for optimal treatment of relapsed ovarian cancer.
Eur J Cancer. 2011; 47 Suppl 3:S104-15 [PubMed]

The proportion of patients with advanced ovarian cancer who relapse has remained high and fairly constant over the last decade. Choosing treatment for recurrent ovarian cancer is complex. Many active therapeutic agents are available, and there are challenges in defining the optimal timing and sequencing of treatments. Furthermore, the explosion in the number of biological agents presents additional challenges in identifying their activity and place in the pathway of treatment. Establishing optimal treatment as monotherapy, or in combination with chemotherapy, or as maintenance treatment requires new approaches to trial design, selecting meaningful endpoints and conducting carefully conducted trials with translational studies. Patients with relapsed ovarian cancer can now survive several years; the aim is to increase this further.

UCL Cancer Institute, University College London, London

Asher V, Lee J, Innamaa A, Bali A
Preoperative platelet lymphocyte ratio as an independent prognostic marker in ovarian cancer.
Clin Transl Oncol. 2011; 13(7):499-503 [PubMed]

INTRODUCTION: Ovarian cancer is associated with high mortality due to presentation at advanced stage and high recurrence following treatment with chemotherapy. Most of the prognostic variables in ovarian cancer, including stage and residual disease, are amenable for assessment only after surgery. Currently there are no established preoperative markers including, CA-125, that can predict overall survival in patients with ovarian cancer. The aim of our study was to evaluate the prognostic significance of the preoperative haematological markers platelet lymphocyte ratio (PLR) and neutrophil lymphocyte ratio (NLR) in patients with ovarian cancer.
METHOD: Preoperative PLR and NLR were evaluated in 235 patients undergoing surgery for ovarian cancer. The prognostic significance of both markers was then determined by both uni- and multivariate analytical methods.
RESULTS: High preoperative PLR (p < 0.001) and NLR (p = 0.001) were significantly associated with poor survival using univariate Cox survival analysis. The median overall survival in patients with a PLR of < 300 was 37.4 months (95% CI 26.1-48.7) and 14.5 months (95% CI 11.7-17.2) in those with a PLR of > 300. PLR (p = 0.03) but not NLR (p = 0.575) retained its significance as a prognostic marker on multivariate Cox's regression analysis, along with stage (p < 0.001) and residual disease (p = 0.015).
CONCLUSION: We have shown for the first time that PLR is a novel independent prognostic marker in patients with ovarian cancer.

School of Graduate Medicine and Health, Royal Derby Hospital

McNeilly AS
Diagnostic applications for inhibin and activins.
Mol Cell Endocrinol. 2012; 359(1-2):121-5 [PubMed]

Inhibin and activins play major roles as paracrine and autocrine signaling molecules in reproduction and development where the main emphasis has been placed in developing potential diagnostic applications. While a role for activin assays in diagnostics has so far been unfounded, ELISAs specific for the biologically active inhibin A and B dimers, and for free inhibin alpha subunits, alone or in combination have found some specific diagnostic applications. Addition of inhibin A to the triple test for Down syndrome in the second trimester of pregnancy, measurement of total inhibin as a marker of certain forms of ovarian cancer in specific circumstances, and inhibin B for male fertility are useful diagnostics. A review of the evidence so far suggests that other applications for inhibin and activin assays have yet to be confirmed, or translated into reliable tools for clinical practice.

MRC Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ

Sala E, Mannelli L, Yamamoto K, et al.
The value of postoperative/preadjuvant chemotherapy computed tomography in the management of patients with ovarian cancer.
Int J Gynecol Cancer. 2011; 21(2):296-301 [PubMed]

Objective: The objectives of the study were to compare the operative assessment of residual disease with the postoperative computed tomography (CT) findings in patients with ovarian cancer who underwent primary surgical cytoreduction or interval debulking surgery to residual disease 1 cm or less and to assess the effect of potential prognostic factors on patient survival.Methods: Patients scheduled for surgery and with an available postoperative CT were eligible for the study. Images were retrospectively analyzed in consensus by 2 radiologists.A 5-point qualitative scoring system was used to evaluate the CT findings (1 = tumor definitely absent, 2 = tumor probably absent, 3 = tumor possibly present, 4 = tumor probably present, 5 = tumor definitely present).Results: Between September 2005 and December 2008, 206 consecutive patients were enrolled; 51 were eligible. In 30 cases (59%), the postoperative CT findings correlated with the surgeon's assessment of residual disease. For the univariate analyses, the only significant prognostic factors associated with overall survival were no residual disease versus residual disease of less than 1 cm as assessed by the surgeon (hazard ratio [HR], 3.06; 95%confidence interval [CI], 1.29--7.27; P = 0.011) and no residual disease versus residual disease greater than 1 cm on CT (HR, 2.57; 95% CI, 1.02--6.48; P = 0.045). The interaction of surgical residual disease and stage 3 was significant (HR, 3.40; 95% CI, 1.42--8.16;P = 0.006) in the multivariate Cox model.Conclusions: There was only 59% correlation between the surgical assessment and post operative CT findings of residual disease in patients reported to have undergone optimal surgery. Stage and residual disease as assessed by the surgeon were significant prognostic factors for overall survival. The value for postoperative CT may lie in those cases with small-volume residual disease (visible but reported as G1 cm) at surgery.

FRCR, University Department of Radiology, Addenbrooke’sHospital, Hills Rd, Cambridge CB2 0QQ

McCluggage WG
Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis.
Pathology. 2011; 43(5):420-32 [PubMed]

Ovarian carcinomas comprise a heterogeneous group of neoplasms, the four most common subtypes being serous, endometrioid, clear cell and mucinous. In recent years, our understanding of the underlying pathogenesis and initiating molecular events in the different tumour subtypes has greatly increased, and although ovarian carcinoma is often considered clinically as one disease, there is now a much greater realisation that the various subtypes have a different natural behaviour and prognosis. At present, adjuvant therapy is mainly dependent upon tumour stage and grade rather than type; however, this is likely to change in the future with the development of new chemotherapeutic agents and targeted therapies and clinical trials are necessary to evaluate the efficacy of different agents in clear cell, mucinous and low grade serous carcinomas, neoplasms which are considered relatively resistant to traditional chemotherapeutic regimes. In this review, the major subtypes of ovarian carcinoma are discussed. It is now firmly established that there are two distinct types of ovarian serous carcinoma, low grade and high grade, the former being much less common and arising in many cases from a serous borderline tumour. Low grade and high grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis rather than low grade and high grade variants of the same neoplasm. Both are usually advanced stage (stage III or IV) at diagnosis. B-raf and k-ras mutations are important molecular events in low grade serous carcinomas while high grade serous carcinomas are almost always associated with TP53 mutation. There is now emerging and compelling evidence that many high grade serous carcinomas (by far the most common subtype of ovarian carcinoma) actually arise from the epithelium of the distal fallopian tube. Future studies regarding the initiating molecular events in the development of this aggressive neoplasm should concentrate on this site. Primary ovarian mucinous carcinomas are uncommon, almost always unilateral and stage I, and largely of so-called intestinal or enteric type. Most arise in a stepwise manner from a pre-existing mucinous cystadenoma and mucinous borderline tumour. Endometrioid and clear cell carcinomas typically present as low stage neoplasms and in many, or most, cases arise from endometriosis; the former are usually well differentiated and there is now evidence that the majority of neoplasms reported in the past as high grade endometrioid carcinoma are of serous type. WT1 is useful in this regard since it is a relatively specific marker of a serous phenotype. It is recommended that different subtypes of ovarian carcinoma are graded using different systems rather than employing a universal grading system.

Department of Pathology, Belfast Health and Social Care Trust, Belfast

Kirkpatrick GJ, Plumb JA, Sutcliffe OB, et al.
Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin.
J Inorg Biochem. 2011; 105(9):1115-22 [PubMed]

Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion (1)H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH(3))(2)} molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'-GMP at temperatures of 60°C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%.

Strathclyde Institute of Pharmacy and Biomedical Sciences, John Arbuthnott Building, 161 Cathedral Street, Glasgow G4 0RE

Stronach EA, Alfraidi A, Rama N, et al.
HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer.
Cancer Res. 2011; 71(13):4412-22 [PubMed] Article available free on PMC after 19/10/2013

Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests that resistant clones exist within a larger drug-sensitive cell population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically derived, intrapatient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 downregulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of histone deacetylase (HDAC) 4, FOLR2, PIK3R1, or STAT1 (P < 0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum-sensitive cells but not in HDAC4 overexpressing platinum-resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum-induced STAT1 activation, and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors [n = 7 of 16 (44%); P = 0.04]. Therefore, clinical selection of HDAC4-overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer.

Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Edinburgh