BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition.

PURPOSE: Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma-mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. PATIENTS AND METHODS: Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. RESULTS: Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation-positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. CONCLUSION: BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.

Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver.

PURPOSE: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. EXPERIMENTAL DESIGN: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. RESULTS: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. CONCLUSION: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents.

Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva.

BACKGROUND: Human papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV markers in a large series of VIN and IVC lesions. METHODS: Histologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA25) (version 1). IVC cases were tested for p16(INK4a) by immunohistochemistry (CINtec histology kit, ROCHE). An IVC was considered HPV driven if both HPV-DNA and p16(INK4a) overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI). RESULTS: Of 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16(INK4a) positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) (N=1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) (N=326) were more likely to be HPV and p16(INK4a) positive (AP=69.5%, CI=63.6-74.8) versus KSCC (AP=11.5%, CI=9.7-13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold). CONCLUSION: Combined data from HPV-DNA and p16(INK4a) testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide.

Venous thromboembolism following gynaecological surgery for suspected or confirmed malignancy.

BACKGROUND: Venous thromboembolism (VTE) is a serious complication following gynaecological surgery, with malignancy placing patients at an even greater risk. AIMS: To review the incidence of VTE following gynaecological surgery for suspected or confirmed malignancy with respect to prophylactic modalities and to assess the incidence and associated risk factors for bleeding complications. METHODS: A retrospective cohort study was undertaken between 2001 to 2006 on 1363 women undergoing surgery for suspected or confirmed gynaecological malignancy. Data on demographic details, diagnosis, radiotherapy/chemotherapy treatment, operative details, and hospital length of stay (LOS), thromboprophylaxis, in-hospital and 3-month readmission rates for deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were collected. RESULTS: Median age was 54 years (IQR 44-66) and hospital LOS 7 days (IQR 5-9). 51.6% had a new malignancy and 33.0% benign disease. All in-hospital VTE events (0.4%; 95% CI 0.2-1.0%) occurred in women with advanced malignancy. VTE rate was 1.5% (95% CI 1.0-2.3%) at 3 months. In-hospital and 3-month non fatal PE occurred in 0.4% (95% CI 0.2-0.9%) and 1.1% (95% CI 0.7-1.8%) respectively, with a fatal PE rate of 0.1% (95% CI 0.04-0.5%). Malignancy (OR 10.3; 95% CI 1.3-80.6; P = 0.026) and duration of surgery (OR 2.1; 95% CI 1.4-3.2; P = 0.001) significantly increased bleeding risk. CONCLUSIONS: In-hospital VTE risk is higher following gynaecological surgery for malignancy than for benign disease, despite the use of thromboprophylaxis. Given the higher non fatal PE rate after discharge and increasing trend towards shorter hospital LOS, extended prophylaxis in these patients should be considered.

Ankyrin repeat domain 1, ANKRD1, a novel determinant of cisplatin sensitivity expressed in ovarian cancer.

PURPOSE: The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics. EXPERIMENTAL DESIGN: Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma. RESULTS: The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P=0.013). CONCLUSIONS: These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.

I want the one for older women - extending the human papillomavirus vaccine population base.

Cervical cancer prevention relies on two different age-specific technologies, and consumers should not be misled about the role of HPV vaccines.

What is the ideal support group? Views of Australian people with cancer and their carers.

AIMS: To explore views on the ideal structure and process of support groups for cancer patients. PATIENTS AND METHODS: From 184 cancer support groups identified in NSW, Australia, 50 were randomly selected within strata of five variations in group structure: homogenous versus heterogenous participants; urban versus rural; community versus hospital setting, leader with cancer experience or not; and with professional training or not. Four hundred and seventy-six group members completed a questionnaire. RESULTS: Participants valued being with others like them, gaining information about cancer and having an effective leader. Groups were seen to be currently failing people from culturally and linguistically diverse backgrounds, and links with oncology health professionals were inadequate. Few clear preferences for structure were expressed, except for the non-exclusion of those with a poor prognosis. Patients tended to prefer the structure of their own group, but patients longer since diagnosis, those with better informal support and carers preferred to meet in the community setting, while men with prostate cancer preferred a medical setting. CONCLUSIONS: Some suggestions for group structure and process can be made on the basis of these findings; however, individual variation suggests that a needs analysis should be made by individual groups.

Cervical cancer screening in a Vietnamese nominal cohort.

BACKGROUND: In New South Wales (NSW) information on migrant status is not collected in routinely recorded cervical screening data, yet some migrant groups, particularly Vietnamese-born women, have a higher incidence of cervical cancer and, purportedly, lower cervical screening rates than Australian-born women. To investigate this, screening rates in a cohort of women with Vietnamese surnames were estimated and compared with survey data. METHODS: A cohort of women with common Vietnamese surnames was extracted from the NSW electoral roll and matched over three periods with data held on the NSW Pap Test Register (PTR), and estimates of cervical screening in the cohort derived. Screening rates for each of the three periods were pro-rated to biennial rates, and time-related changes compared. Screening rates in the cohort were also compared to those in Vietnamese migrant respondents to a population-based health interview survey. RESULTS: Estimated biennial screening rates in the overall Vietnamese nominal cohort of women aged 20-69 years were significantly and substantially lower than those for NSW overall, by 10-12 percentage points. Screening rates in the Vietnamese cohort were found to increase over the study period, from 44% for 1997/98 to 47% for 1998/99. While the biennial screening rate for 1998 in the nominal cohort was 19 percentage points lower than the self-reported surveyed screening rate of 63%, the relative screening ratios between Vietnamese and all NSW women were similar for both data sources. CONCLUSION: This study demonstrates the feasibility of estimating and monitoring cervical screening participation in minority groups with distinctive names using a Pap Test Register and information from a population register.

Molecular genetics and endometrial cancer.

Endometrial cancer is a common gynaecological malignancy in the industrialised world. Unopposed stimulation of the endometrium by oestrogens is the classic aetiological factor associated with the development of this malignancy. However, not all are associated with oestrogen exposure and two different clinicopathological types can be distinguished: the oestrogen-related of endometrioid type (type I) and the non-oestrogen-related of non-endometrioid type (mainly papillary serous or clear cell carcinomas) (type II). Recent advances in the knowledge on the molecular genetics of endometrial cancer have shown that the molecular changes involved in its the development differ in oestrogen-dependent type I and non-oestrogen-dependent type II. Type I carcinomas frequently show mutations of DNA-mismatch repair genes (MLH1, MSH2, MSH6), PTEN, k-ras and beta-catenin genes whereas type II malignancies are characterised by aneuploidy, p53 mutations and her2/neu amplification. This article reviews the latest findings concerning common gene mutations involved in the development and progression of endometrial cancer.

Gynaecological malignancies in pregnancy: a review.

Gynaecological malignancies frequently occur in women of reproductive age and are estimated to complicate approximately one in 1000 pregnancies. The incidence of gynaecological malignancies during pregnancy is expected to rise as more women delay childbearing into their later reproductive years, and maternal age is the most powerful predictor of cancer risk. Pregnancy-associated malignancies present significant challenges as a result of the conflict between optimal maternal therapy and fetal well-being. The lack of prospective randomised treatment studies has prevented the development of clinical guidelines for most of the issues complicating the management. In the present review, recent diagnostic and treatment strategies for cervical, ovarian, vulvar and endometrial carcinomas during pregnancy are presented.