OVARIAN CANCER and US

Wednesday, August 12, 2015

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

abstract

Purpose The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer.

Patients and Methods The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis.

Results In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001).

Conclusion These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

(U.S.)How Employment Discrimination Laws Protect Cancer Survivors

Employment Discrimination Laws

Associations between the Genetic Polymorphisms of Osteopontin Promoter and Susceptibility to Cancer in Chinese Population: A Meta-Analysis

open access

Discussion

Osteopontin is a member of small intrgrin-binding ligand N-linked glycoproteins (SIBLINGs) family. There are many pieces of evidences indicating that osteopontin profoundly regulate the development and progression of various tumors. Additionally, OPN expression was significantly higher in human cancers tissues than in matched normal tissues and it was significantly associated with nodal metastasis and more advanced clinical stage. Therefore, numerous publications have tested OPN as a biomarker for cancer invasiveness [31–34]. However, the associations with tumorigenesis have not been proved well. Polymorphisms in the OPN gene, SPP1, may potentially alter the expression of OPN and then modulate the risk for cancer. In recent years, SNPs have been identified as a powerful tool for predicting some complex diseases. However, previous genetic epidemiological studies about the associations between OPN gene polymorphisms and the risk of human cancer are limited, and the results were inconclusive. To our knowledge, this is the first meta-analysis which investigated the possible correlations of rs11730582 (-443 T>C), rs17524488 (-156G>GG), and rs28357094 (-66T>G) polymorphisms in the SPP1 gene with cancer susceptibility.
Our results revealed that -443T>C polymorphism might have no relation with pathogenesis of cancer. And we found that different studies had inconsistent results about this polymorphism even for the same cancer. For example, Chen JX [22] said that in a recessive genetic model TC + CC genotypes significantly decrease the risk of glioma when compared with TT, but Shen ZP [26] considered that the glioma patients had markedly high frequency of -443CC genotype than controls. Another two studies [29,30] showed that there was no significant difference in the distribution of -443 between cancer patients and controls. What’s more, large heterogeneity was found in four gene models (P<0.0001). Previous meta-analysis about human cancer risk found that the cancer type might contribute most to the source of heterogeneity [35,36]. In this study, the subgroup analysis on basis of cancer types was not calculated because of the limited number of studies. So this result should be interpreted with caution.
For -156G>GG, our study found that GG allele was at significant high risk for cancer under all four genetic models, and this result was confirmed among studies in HWE. When we exclude the study of Mu GY [25] which may be source of the heterogeneity, the results remain unchanged. That means the SNP of -156G>GG may considerably act a potential candidate of biomarker for cancer risk.
The meta-analysis of -66T>G include eight studies, however, two studies [24,29] that was not estimable in meta-analysis (Fig 2). The results of polymorphism in a dominant model showed that the genotypes TG+ GG significantly decreased the risk of cancer when compared with TT. Noteworthy, the association was disappear when exclude the study of Xu Q [27] that may be the source of the heterogeneity. So, the result is instable and further studies are necessary to clarify the association.
High OPN expression in the primary tumors is associated with cancer risk, metastasis and poor clinical outcome [37–39]. The previous study showed that -443 promoter region exerts influence on OPN gene expression in melanoma cells [40]. In our including studies, four studies [10,25,26,28] observed the association of OPN levels and SPP1 polymorphisms. Mu GY [25] and Zhang R [28] observed that the high OPN expression was more frequent in samples from -443 CC carriers than TT carriers, However, Shen ZP [26] found that none of the polymorphisms affected the serum OPN levels, Wang JL [10] thought that carriers of CC and CT genotype of -443 presented lower serum osteopontin levels than those of TT genotype. Among the four studies only two gave the accurate data, so we cannot offer further statistics. The result may be caused by following reasons: (1) the SPP1 polymorphisms affected the tumor OPN expression level, but not the serum OPN level; (2) the association is indeed related and further studies are just needed; (3) SPP1 polymorphisms make no difference in OPN level.
Some advantage could be highlighted in this meta-analysis. On one hand, this research shed lights on the relationship of genetic polymorphisms in SPP1 gene and the increased susceptibility to human cancers in Chinese population systematically. One the other hand, the exhaustive inclusion criteria and articles on wide range of cancers enhanced the power and persuasion of our conclusion. Furthermore, all literatures included had acceptable quality scores (scored at least 6). Meanwhile, we were also aware of several limitations of our study. First, all eligible studies come from China and the patients are Chinese population. Second, the number of the studies, especially for -66T>G polymorphism, was not sufficiently large, Third, for -443T>C polymorphism, the heterogeneity was big, the comprehensive analysis should be explain with caution.

Conclusion

This meta-analysis suggests that in Chinese population the -156G>GG polymorphism of SPP1 might be a risk factor for human cancers, while -443T>C mutation is not associated with cancer risk. For -66T>G polymorphism, it may be a protective factor for human cancers.

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial - The Lancet Oncology

Background

Chemotherapy-induced nausea and vomiting is a common side-effect of many antineoplastic regimens and can occur for several days after treatment. We aimed to assess the neurokinin-1 receptor antagonist rolapitant, in combination with a serotonin (5-HT₃) receptor antagonist and dexamethasone, for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide.

Tuesday, August 11, 2015

Screening for Lynch syndrome and referral to clinical genetics .... UK

open access
Screening for Lynch syndrome and referral to clinical genetics by selective mismatch repair protein immunohistochemistry testing: an audit and cost analysis

Take home messages

Lynch syndrome (LS) screening is currently fragmented and inconsistent in the UK.
Reflex mismatch repair immunohistochemistry (MMR IHC) on all colorectal cancer (CRC) is now recommended by the Royal College of Pathologists, but MMR IHC status remains a non-core item for all CRCs due to resource implications.
LS screening through selective MMR IHC model performed for prognostication in stage II CRC can be implemented when funding is limited, especially when expenditure has to be justified by impact on oncological decisions.

Pseudoprogression and Immune-Related Response in Solid Tumors

open access

....Multiple recent clinical trials using antibodies to PD-1 and PD-L1 in the treatment of advanced solid tumors have been completed and published,^10–22 enabling broader evaluation of pseudoprogression across solid tumors. The majority of these clinical trials evaluated the safety and efficacy of immune checkpoint blockade in the treatment of patients with melanoma. However, additional studies were conducted in patients with bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, lung cancer, pancreatoduodenal cancer, ovarian cancer, renal cell cancer, sarcoma, and uterine cancer. The observed incidence of distinct immune responses across different solid tumor types is provided in Table 1.

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

abstract

Results In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001)........ furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001).

JCO Art of Oncology: Key Opinion Leaders

Key Opinion Leaders

Diagnosis and management of upper tract urothelial carcinoma - Beyond the Abstract (Lynch Syndrome patients)

note: of interest to Lynch Syndrome patients

upper tract urothelial carcinoma

Management of toxicities following pelvic irradiation for gynaecological cancers

abstract (full access is by paid subscription)

Purpose of review: With increasing numbers of cancer survivors, management of the consequences of treatment is a major clinical problem. This article discusses recent advances in preventing and managing radiotherapy-related toxicity.

Recent findings: Often underreported in clinical studies, radiation toxicity should be assessed with validated assessment tools to assess impact on quality of life. Prevention strategies targeting reactive oxygen species and proinflammatory cytokines show promise. Bowel toxicity is the most common late effect, and algorithm-led investigation and management can significantly improve outcomes. Oral and intravesical therapies are options for bladder toxicity if conservative measures fail.

Summary: With better understanding of the mechanisms of acute and chronic radiation-induced changes, more effective treatments are now possible. Following pelvic radiotherapy, patients should be proactively assessed for early intervention by a specialist multidisciplinary team.

Genomics: selected articles - Lynch Syndrome

Lynch Syndrome

Low-grade epithelial ovarian cancer: a number of distinct clinical entities?

abstract

PURPOSE OF REVIEW:

The purpose of this study is to summarize the contemporary understanding of low-grade epithelial ovarian cancers.

RECENT FINDINGS:

Low-grade serous ovarian cancer is biologically distinct from high-grade serous ovarian cancer. It is associated with a high incidence of K-RAS and B-RAF mutations. Although described as indolent due to median progression-free and overall survivals of 20 and 99 months, respectively, with a median age of diagnosis of 43 years, it accounts for a significant number of patient-years lost. Retrospective studies suggest response rates of 5% for chemotherapy and 9% for antioestrogen therapy. A prospective study of the mitogen-activated protein kinase kinase inhibitor selumetinib (response rate 15%) and retrospective bevacizumab studies suggest that these may be more effective approaches.Limited retrospective clinical data and even more sparse molecular data suggest that similar distinctions may exist between low-grade endometrioid and mucinous ovarian cancers and their respective high-grade counterparts, but more research is required in order to clarify the biological differences and the implications that these have for management.

SUMMARY:

The results of phase III mitogen-activated protein kinase kinase inhibitor studies in low-grade serous ovarian cancer and further clinical and biological assessment of low-grade endometrioid and mucinous ovarian cancers are urgently required.

Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors

open access

Abstract
Conclusions

The diversity of mutational targets suggests multiple routes to tumorigenesis in this heterogeneous group of tumors that is generally distinct from other ovarian subtypes.

Background

Epithelial ovarian tumors have historically been treated as a homogenous group in the clinic, despite clear histopathological and molecular data showing that distinct subgroups exist: serous, endometrioid, clear cell and mucinous. High-grade serous and low-grade serous tumors comprise distinct groups, while endometrioid and clear-cell histologies are different again from serous but with some overlapping genetic events. It is now clear that these molecular distinctions reflect differences in site of origin, with high-grade serous tumors now thought to arise from the fallopian tube fimbriae, low-grade serous tumors from the ovarian epithelium, and clear cell and endometrioid tumors arising from endometriosis, which itself is derived from the endometrium. However, the origin of the mucinous group remains controversial. Many mucinous ovarian tumors (MOTs) formerly classified as primary are now recognized to have been mis-diagnosed metastases from predominantly gastrointestinal or endocervical sites. However, some mucinous tumors do appear to be ovarian primaries, particularly benign and borderline tumors, which generally have a good prognosis not consistent with a metastatic tumor......

Conclusions

......The initiating cell type of mucinous tumors presenting on the ovary remains to be determined; the heterogeneity of the mutations observed here as well as the mutational spectrum suggests that the ovarian surface epithelium is unlikely to be the only source.

Monday, August 10, 2015

Canadian company (Canada Drugs) charged in the U.S. with selling unapproved, counterfeit drugs

The Globe and Mail

.....An online Canadian pharmacy sold $78-million worth of unapproved, mislabelled and, in two cases, counterfeit cancer drugs to doctors across the United States over three years, U.S. government prosecutors said.....

..... The 14-year-old Winnipeg company’s website describes itself as offering low prices on medicine from Canada, the U.K., Australia and New Zealand. A company spokesman and its attorney did not return calls Monday.

The medicines named in the criminal indictment are mainly clinical drugs that treat cancer or the effects of chemotherapy. Nearly all of the drugs are legal in the U.S. when sold by FDA-approved manufacturers and marketers.

Health Canada suspended the company’s establishment licence in June, 2014, over what it called “significant concerns” about its manufacturing practices.....

Data set for reporting of ovary, fallopian tube and primary peritoneal carcinoma: recommendations

Abstract

Data set for reporting of ovary, fallopian tube and primary peritoneal carcinoma: recommendations from the International Collaboration on Cancer Reporting (ICCR)

A comprehensive pathological report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but these vary in their content. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, with the aim of developing an evidence-based reporting data set for each cancer site. This will reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of primary ovarian, fallopian tube and peritoneal carcinoma and present the ‘required’ and ‘recommended’ elements to be included in the report with an explanatory commentary. This data set encompasses the recent International Federation of Obstetricians and Gynaecologists staging system for these neoplasms and the updated World Health Organisation Classification of Tumours of the Female Reproductive Organs. The data set also addresses issues about site assignment of the primary tumour in high-grade serous carcinomas and proposes a scoring system for the assessment of tumour response to neoadjuvant chemotherapy. The widespread implementation of this data set will facilitate consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and hopefully will result in improved patient management.

Population Landscape of Familial Cancer

Scientific Report - Nature - open access

.... Our study showed that the existence of affected family members is an important risk factor for all cancer types. For common cancers familial risk even increased with the number of affected family members. Until now, over 100 cancer predisposing variants have been identified and in addition over 300 low-risk loci have been mapped¹⁵. However, only a small proportion of familial cancer can be explained by the established genetic predisposition, and the proposed risk estimates vary extensively¹⁶. For example, in colorectal cancer some studies have assumed that mismatch repair gene defects (hereditary non-polyposis colon cancer) account for most of familial aggregation¹⁷, but the recent exome sequencing data put the figure at 11% of familial cancer and early onset cases¹⁸. In clinical genetic counseling mutation testing is offered only for a few high-risk cancer predisposing genes.......

..... Furthermore, high-risk cancer predisposing genes such as BRCA1/BRCA2 associated with familial breast cancer or mismatch repair genes involved in Lynch syndrome (hereditary non-polyposis colon cancer) may account for significantly increased risk of breast and colorectal cancers in the cluster of affected parents and siblings. Interestingly, the corresponding risks for two affected siblings were also elevated, but only modestly and the difference was significant only for breast cancer......

In conclusion, our results show that familial risk is a shared feature of all cancers and for many cancers multiple affected family members signal a high or very high risk that would necessarily require medical action. Some of such families are likely carriers of known high-risk cancer predisposition genes. However, the major proportion of familial cluster is probably caused by genes that remain to be discovered. Nevertheless, medical or behavioral intervention may be indicated, including screening recommendations or avoidance of carcinogenic exposures. The readily available information of family history deserves more attention in the first oncology contacts and established referral mechanisms for clinical counseling to evaluate screening and prevention strategies individually tailored to patients and their family members.